[Frontiers in Bioscience 16, 865-897, January 1, 2011]
Bone morphogenetic protein and bone metastasis, implication and therapeutic potential Lin Ye1, Malcolm D. Mason1, Wen G. Jiang1
1Metastasis and Angiogenesis Research Group, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
TABLE OF CONTENTS
1. ABSTRACT
Bone metastasis is one of the most common and severe complications in advanced malignancies, particularly in the three leading cancers; breast cancer, prostate cancer and lung cancer. It is currently incurable and causes severe morbidities, including bone pain, hypercalcemia, pathological fracture, spinal cord compression and consequent paralysis. However, the mechanisms underlying the development of bone metastasis remain largely unknown. Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and are pluripotent factors involved in the regulation of embryonic development and postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. Since they are potent regulators for bone formation, there is an increasing interest to investigate BMPs and their roles in bone metastasis. BMPs have been implicated in various neoplasms, at both primary and secondary tumors, particularly skeletal metastasis. Recently studies have also suggested that BMP signaling and their antagonists play pivotal roles in bone metastasis. In this review, we discuss the current knowledge of aberrations of BMPs which have been indicated in tumor progression, and particularly in the development of bone metastasis.
2. INTRODUCTION
Bone metastases are most commonly seen in prostate, breast and lung cancer, which are leading malignancies in female and/or male having the highest incidence and mortality rates (1-3). Bone metastasis usually leads to severe morbidities, which always persist until the death of patients, including bone pain, hypercalcemia, pathological fracture, spinal cord compression and consequent paralysis. In bone metastases, along with growth of cancer cells, oesteoblastic and oesteolytic activities are stimulated simultaneously or one occurs in predominance. Although osteoblastic lesions are commonly seen in prostate cancer whilst osteolytic lesions frequently occur in breast cancer, lung cancer and renal cancer, certain proportion of bone metastases have demonstrable mixtures of oesteoblastic and oestolytic lesions (4, 5). Since Dr. Paget proposed 'seeds' (metastatic cancer cells) and 'soil' (metastatic site) hypothesis for cancer metastasis in 1889, clinicians and scientists have spent immense effort to understand how the seeds and soil work together and subsequently develop metastases. As one of the most common metastatic sites, bone metastasis has been investigated extensively from molecular and histological characteristics to diagnosis and management. Knowledge about molecular mechanisms underlying osteoblast and osteolytic lesions has been expanded rapidly over last few decades. Parathyroid hormone-related protein (PTHrP), interleukin (IL)-11, IL-8, IL-6, and receptor activator of nuclear factor-κB ligand (RANKL) produced by metastatic cancer cells play critical roles in osteolytic bone metastases (6-9). On the other hand, endothelin-1, BMPs, prostaglandins and TNFα have been implicated in the development of osteoblastic lesions (10, 11). However, molecular mechanisms underlying the predisposition of the particular malignancies and subsequent colonisation and development of metastatic tumors remain largely unknown. As bone morphogenetic proteins (BMP) are potent regulators for bone formation, there is an increasing interest to investigate BMPs and their roles in bone metastasis. BMPs belong to the TGF-beta superfamily and are pluripotent factors involved in the regulation of embryonic development and postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. BMPs have been implicated in various neoplasms, at both primary and secondary tumors, particularly skeletal metastasis. Recently studies have also suggested pivotal roles played by BMP signaling and their antagonists in bone metastasis. In this review, we discuss the current knowledge of BMPs signaling, aberrations which have been indicated in tumor progression, and particularly in the development of bone metastasis.
3. BONE MORPHOGENETIC PROTEINS
Bone morphogenetic proteins (BMPs) belong to transforming growth factor-beta (TGF-β) superfamily, which were first named by Dr. Urist for their capacity to induce ectopic bone formation (12). BMP proteins were not purified and cloned until late 1980s (13-16), to date, more than 20 BMPs have been identified in humans (Table 1). In addition to their ability in facilitating intramembraneous/endochodral bone formation and formation of cartilage, BMPs play crucial roles in diverse developmental processes and homeostasis of various tissues and organs including tooth, kidney, prostate, breast, skin, hair, muscle, heart and neuron through coordinating cellular differentiation, proliferation, survival and apoptosis. Certain BMPs have also been shown to be involved in the maintenance of the metabolism of glucose and iron (Table 1).
3.1. Structural characteristics of BMPs
BMPs are synthesized as large precursor molecules, consisting of an amino-terminal (N-terminal) pro-region and a carboxy-terminal (C-terminal) ligand (13, 16, 17). Each BMP ligand has seven conserved cysteines at the C-terminal, in which six cysteines construct a cysteine knot, and the seventh cysteine contributes to the dimerisation (18). It has been shown that some of the proprotein convertases (PCs), such as furin, proprotein convertase subtilisin/kexin type 6 (PCSK6) and proprotein convertase subtilisin/kexin type 5 (PCSK5) which belong to a subtilisin-like proprotein convertase family, can proteolytically activate BMP precursors at the sequence of R-X-K/R-R or R-X-X-R (19-22). The pro-region of the precursor BMP protein controls the stability of the processed mature protein, and the amino acid motif adjacent to the cleavage site determines the efficiency of cleavage (20). Amongst the BMPs, growth differentiation factor-9 (GDF9) and BMP15 (GDF9B) may be an exception and have only six cysteines in the mature ligand which lacks the seventh cystein. This characteristic of BMP15 and GDF9 may help to define its ligand binding property to its receptors (23). The pro-region of some BMPs remains noncovalently associated with the mature ligand even after secretion from the cell, for example: GDF-8 and BMP9 (24, 25). Once processed and activated, BMP proteins are biologically active both as homodimer, and as heterodimer molecules, in which two chains are connected by disulfide bonds. Interestingly, the heterodimers of BMP4/7, BMP2/6, BMP2/7 and BMP7/GDF7 may be more effective than their respective homodimers (18, 26-28).
3.2. BMP receptors
BMP signals are mediated by receptors which are dedicated to TGF-β signaling, and include type I and type II serine/threonine kinase receptors. Seven type I and five type II receptors have been identified for TGF-β signaling in humans (Table 2). Six of the type I receptors and three of the type II receptors have been shown to mediate BMPs signaling (Figure 1) (29). BMPR1A, BMPR1B and BMPR2 are specific for the BMPs; whilst ACVRL1, ACVR1, ACVR1B, ACVR2B, and ACVR2A are also the receptors for activin; TGFBR1 (ALK5) is known as the type I receptor for TGF-β1, 2 and 3. Both receptor types are required for downstream signaling to occur; the type-I receptors are unable to bind their ligands without the presence of the type-II receptors, while the latter is incapable of signaling without their type-I counterparts (30).
Both types of BMP receptors consist of a N-terminal extracellular ligand binding domain, a single transmembrane region and a C-terminal serine/threonine kinase domain (31). The structure of the extracellular domain (ECD) of both receptors is similar. It has several conserved cysteines, which are important for the formation of characteristic three-dimensional structures. The ECD domain of type II receptors has three finger toxin folds, composed of three β-sheets and held together by a cluster of disulphide bonds to form the conserved scaffold (32, 33). The ECD domain of Type I receptor, for example BMPR-IA consists of two β-sheets and one α-helix which is different from the type II. This may be profound for their specific ligand binding (33). In addition to the conserved cysteine motif, the C-terminal of both type I and type II receptor ECDs have conserved clusters of hydrophobic residues, critical in ligand binding. The structure of this groove of residues is common in both types of receptors, but is less distinct in type-II receptors. In addition, all type-I receptors apart from ALK-1, have a large protruding hydrophobic residue on the core α-helix which fits into a hydrophobic pocket of the ligand. This process is known as the 'knob into hole' motif of type-I receptor ligand binding (33).
The intracellular region of the type I receptors, but not type II receptors, contains a highly conserved glycine and serine rich domain (GS domain), which is located in the intracellular juxtamembrane region of the receptor (31, 34). Type II receptors recruit type I receptors by phosphorylating the GS domain of type I receptor during signal transduction. The intracellular cytoplasmic region of both types of receptors consists of an enzymatic serine/threonine kinase domain critical in transducing the downstream signal of BMPs. This transphosphorylation is critical as it is required for activation of the type-I receptor, and hence downstream signaling. The type-II receptor kinase domain on the other hand, is constitutively active and hence does not require any activational phosphorylation event (35). In addition, type-II receptors have a short serine-threonine rich tail at the C-terminal of their kinase domains, not seen in type-I receptors (31).
3.3. Intracellular signal transduction
In absence of ligand binding, a small proportion of type I and type II receptors are present as preformed homodimers and heterodimers. Upon binding with ligands, oligomerisation of the receptors rapidly lead to conformational changes of the receptor complexes. This forms a ligand-receptor complex consisting of a homodimer/heterodimer of BMP ligands, Type-I and Type-II receptors. The Type-II receptors then transphosphorylates the GS domain of the Type-I receptors and leads to activation of downstream cascades (36). If the BMP ligand binds simultaneously to the preformed hetero-oligomeric complexes (PFC), this leads to activation of the Smad dependent pathway(37, 38). It includes recruitment of the pathway-restricted Smads (R-Smads, Smads1, 2, 3, 5 or 8), and regulates the transcription of target genes, this is known as the Smad dependent pathway. Unlike other members of TGF-β superfamily, BMPs have a higher affinity for the Type-I receptors, rather than the Type II receptors. Thus, BMP ligand can also bind to ALK3 or ALK6, and then recruits BMPRII into a hetero-oligomeric complex (BMP-induced signaling complexes, BISC), this leads to the activation of the Smad independent pathway (37, 38). Type I and type II BMP receptors are indispensable for both Smad dependent and independent pathways (Figure 2).
3.3.1. Smad dependent pathway
Smad proteins are important intracellular signaling molecules downstream of the BMP receptors. They are homologues of the originally identified Mad and Sma proteins, found in Drosophila and C. Elegans, respectively (39). To date, eight Smads have been identified in humans, and comprise three subgroups: pathway restricted Smads (receptor regulated Smads) (referred to as R-Smads which include Smad 1, 2, 3, 5 and 8), common mediator Smad (Co-Smad, Smad4), and inhibitory Smads (I-Smads, Smad 6 and 7) (38, 40). R-Smads 1, 5 and 8 are substrates of the type I receptors, including ALK-1, ALK-2, ALK-3 and ALK-6; whereas R-Smads 2 and 3 are substrates of the type I receptors including ALK-4, ALK-5 and ALK-7 (40-43). All Smad proteins share considerable homology in their primary sequences. In addition to a non-conserved proline rich linker region, R-Smads and Co-Smad contain two highly conserved Mad homology domains: the Mad homology 1 (MH1) domain in the amino-terminal part and the Mad homology 2 (MH2) domain at the carboxy-terminal. The MH1 domain can bind to specific DNA sequences, and the MH2 domains are responsible for homo- and heteromeric complex formation. The MH1 domain regulates transcription by interacting with other transcription factors, and contains a highly conserved β-hairpin eleven residues in length, which can directly bind to DNA through the major groove (44). In the case of the I-Smads, the MH1 domain is very short, with highly distinct sequences and is not able to bind DNA. Furthermore, the MH1 domain of inactive Smads acts as a repressor of the MH2 domain, by preventing it from forming a complex with Smad4. Phosphorylation of the C-terminal MH2 domain by the type I receptor appears to unfold the two domains and alleviates the inhibition of MH1 (39). In Smad3, basic helix 2 consists of a KKLKK sequence that acts as a nuclear localisation signal and hence is critical during Smad3 nuclear translocation (44). The MH2 domain is multifunctional and provides the Smads with their specificity and selectivity, as well as transcriptional activity. In addition, the MH2 domain is critical in oligomerisation and when activated, Smads can form homo-oligomeric complexes by interacting through their MH2 domains (45). Finally, the MH2 domain is also responsible for specific interactions with type-I receptors. This is due to a pocket of basic residues that acts as a docking site for the phosphorylated GS domains of these receptors (45). Smad4 however does not interact with the receptors as it has an inserted element and instead Smad4 acts as a docking site for other R-Smads. The linker region of Smads meanwhile is variable in sequence and length and also contributes to the oligomerisation of Smads. In addition, phosphorylation of four PXS/TP motifs within the linker region by MAPK acts as a mechanism to prevent the accumulation of Smads in the nucleus (46). The proline rich PPXY (PY) sequence allows for interaction with WW motif containing proteins involved in Smad degradation (47). R-Smads contain the C-terminal Ser-Ser-X-Ser (SSXS) motif which is phosphorylated by the Type I receptor during signal transduction of BMPs (38). Of the R-Smads, Smads 2 and 3 are known as TGF-β/activin activated Smads, whereas Smads 1, 5 and 8 are the BMP activated Smads (48). Smad2/3 has been shown to colocalise to the cell membrane via a FYVE domain Smad interacting protein known as Smad-anchor for receptor activiation (SARA). During induction of TGF-β signaling, SARA acts to recruit Smad2 to its type-I receptor, resulting in its phosphorylation and dissociation from SARA, allowing it to complex with Co-Smad4 (49). Smad4 acts to form a heteromeric complex with the R-Smads and translocates them to the nucleus in order for them to regulate transcription of their target genes.
Following Smad-complex translocation into the nucleus, R-Smads interact with other proteins including transcriptional coactivators and repressors in order to bind to specific DNA sequences and regulate expression of target genes, inlcuding Id1-3, Smad6/7, type-I collagen, JunB and Mix.2. Smad1 binds with low affinity to SBEs and preferentially binds to GC-rich boxes with sequence GCCGNCGC (50). Smad2 and 3 in complex with Smad4 bind specifically via their MH1 domains to Smad binding elements (SBE) with AGAC/GTCT sequences found in target genes' promoter and enhancer (51).
3.3.2. Smad independent pathway
Unlike other members of TGF-β superfamily, BMPs have a higher affinity for the Type-I receptors, rather than the Type II receptors. Thus, BMP ligand can also bind to ALK3 or ALK6, and then recruits BMPRII into a hetero-oligomeric complex (BMP-induced signaling complexes, BISC), this leads to the activation of the Smad independent pathway (37, 38). During intracellular signal transduction, the X-linked inhibitor of apoptosis protein (XIAP) functions as an adaptor protein bridging between the Type I receptor and TGF-ß activated binding protein (TAB1/2/3), which is an activator of the MAPKKK TGF-ß activated tyrosine kinase 1 (TAK1) (52-54). The activation of TAK1 can lead to activation of p38, a mitogen-activated protein kinase (MAPK) (37, 55, 56). TAK1 can also activate Jun N-terminal kinases (JNKs), NF-kappaB (NF-kB) and Nemo-like kinase (NLK) (57-59). TAK1 normally induces apoptosis by activating JNK or P38 MAPK pathways. However, in Xenopus embryos, the BMP signal was shown to interact with XIAP to inhibit TAK1 associated apoptosis by impeding the action of caspases (53).
3.4 Regulatory system of BMP signaling
The regulation of BMP signaling may occur extracellularly during the process of ligand binding to the receptors, or intracellularly during signal relay or finally, affect regulation of their target genes (Figure 3). BMPs have also been shown to regulate their function through a negative feedback loop, in which the pseudoreceptor, Inhibitory Smads (Smad 6 and 7) antagonists of BMPs, appear to be involved (60).
3.4.1. Extracellular regulatory factors
3.4.1.1. BMP antagonists
The most important molecules to influence BMP signaling extracellularly are the BMP antagonists. BMP antagonists exert their influence over BMP and BMP receptors in two ways: direct competition between the antagonists and BMPs, and regulation of expression of the antagonists by BMPs themselves. The antagonists can bind to BMP receptors competitively, and block/inhibit the effect of the BMPs. For example, competition between Noggin and BMP4 regulates dorsalization during Xenopus development (61). On the other hand, noggin expression in osteoblasts can be induced by BMP2, 4 and 6. Therefore, the BMPs are able to modulate their effect via a negative feedback loop by upregulation of the expression of their antagonist (62). Recently, this feedback regulation of BMP antagonists by BMP7 has also been indicated in prostate cancer (63).
3.4.1.2. Pseudoreceptor
Besides the BMP antagonists, there are other mechanisms by which BMP signaling is regulated extracellularly, such as co-receptors and pseudoreceptors. BMP and activin membrane bound inhibitor (BAMBI) is a pseudoreceptor for serine-threonine kinase receptor. BAMBI has an extracelluar domain similar to that of the type I receptors, but lacks the intracelluar serine/threonine kinase domain. BAMBI binds to ligand competitively, and then inhibits signaling by BMPs and other TGF-β molecules (64). BMP4 can also induce the expression of BAMBI in mouse embryonic fibroblasts (65), in doing so, BMP4 creates a negative feedback loop to regulating BMP function. Some transmembrane tyrosine kinase receptors have been reported to interact with BMP receptors and regulate their signaling. TrkC, a neuronal tyrosine kinase receptor, has been shown to directly bind to BMPR-II, inhibiting its interaction with type I receptors and downstream signaling (66). Another tyrosine kinase receptor Ror2 forms heteromeric complex with BMPR-IB in a ligand independent manner leading to an inhibition of downstream Smad1/5 signaling by GDF-5 (67).
3.4.1.3. Co-receptors
Along with the negative regulators, like other members of the TGF-β superfamily, there are co-receptors for BMP ligands, which positively enhance their signaling. The repulsive guidance molecule family including RGMa, RGMb, and RGMc, are coreceptors for BMP2 and BMP4, and enhance their signaling (68-70). RGMb, also known as DRAGON, is the first co-receptor reported for BMP, and is a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family. DRAGON binds directly to BMP2 and BMP4, but not BMP7 or other TGF-β ligands. The interaction between DRAGON and BMPs enhances the signaling and ultimately leads to a stronger biological response from the cell. Interestingly, this enhanced effect due to the DRAGON/BMP interaction can be reduced by the BMP2/4 antagonsit, Noggin (68). cGMP-dependent kinase I (cGKI) has also been shown to interact with and phosphorylate BMPR-II, leading to enhancement of BMP receptor signaling (71).
3.4.2. Intracellular regulatory factors for Smad signaling
Following the activation by the type I receptor, R-Smads relay the signal into the nucleus and subsequently regulate target genes. A number of proteins existing in the cytoplasm and nucleus interact with R-Smads and therefore can act to coordinate their signaling.
3.4.2.1. Inhibitory Smads (I-Smads)
I-Smads are structurally divergent from the rest of Smads. They act as negative regulators of TGF-β signaling by binding to type I receptors, thereby preventing R-Smad activation, and also compete with Smad4 for hetero-complex formation. Smad7 is responsible for inhibiting TGF-β/activin and BMP signaling, whereas Smad6 is specific for BMP signaling (72, 73). Smad6/7 inhibit signal transduction of BMPs, by inhibiting activation of Smad 1 and 5 by the BMP Type I receptor. Smad6/7 also inhibit the heterodimerization between Smad1/5 and Smad 4 (73, 74). The inhibition can be enhanced through a feedback up-regulation of Smad6/7 by BMPs stimulation (75, 76). However, the inhibitory effect on BMP signaling by I-Smads can also be regulated. The associated molecule with the SH3 domain of STAM (AMSH) is a direct binding partner for Smad6 and has been found to inhibit the interaction between Smad6 and the activated BMP type I receptor, thereby allowing more efficient BMP receptor-induced phosphorylation of R-Smads. In addition, AMSH was found to interfere with the interaction between Smad6 and the activated R-Smad. Thus, AMSH promotes BMP signaling by negatively regulating the function of I-Smads (77).
3.4.2.2. Smad interacting proteins
As Smads generally bind SBEs with low affinity they need to interact with and be recruited by several other transcription factors. The first of these proteins to be identified was Forkhead box HI (FOXHI) which specifically recruits activated Smad2/4 to promoters (78). Others include P53 (79), Runx transcription factors (80), Smad interacting protein-1 (SIP-1) (81), ATF-2 (82) and YYI transcription factors which repress expression of genes including PAI-1 and Id-1 (83).
In addition, some transcriptional co-activators and repressors have also been reported to regulate Smad signaling by interacting with the MH2 binding domain of Smads. P300 and CREB-binding rotein (CBP) are histone acetyl transferase (HAT) proteins and interact with Smads to enhance transcription of their target genes by increasing the accessibility of the transcriptional machinery (84). Transcriptional corepressors include TG interacting factor 1 (TGIF1), TGIF2, ecotropic viral integration site-1 (Evi-1), Ski and Ski related novel gene (SnoN) which interact with Smad3/4 when they bind to the SBEs and recruit histone deacetylases (HDACs) to induce nucleosomal condensation and repress transcription of target genes (85-88). Sloan-Kettering retrovirus (Ski) binds Smad 1, 2, 3, 5 and 4 and inhibits BMP signaling (86, 89, 90). The transducer of ErbB-2 (Tob) is probably associated with the MH2 domain of Smad 1, 5, 6, 7 and 8 (91, 92). Induction of TGF-β signaling, results in Ski and SnoN degradation, allowing Smad3/4 to induce transcription (93-95).
3.4.2.3. Molecules that regulate degradation of the Smads
The concentration of available Smads in the intracellular pool is regulated by HECT type E3 ligases known as Smad Ubiquitination Regulatory Factors (Smurf) 1 and 2. The WW motifs of Smurfs interact with the PY domain in the linker region of R-Smads, inducing their degradation by the proteosome, which results in inhibition of TGF-β family signaling (96). Smurf 1 can directly interact with Smad 1/5, and facilitate their degradation (97). It can also indirectly interact with the BMP type I receptor through I-Smad 6 and 7, and induce ubiquitination and degradation of the receptors (98). TNF has been shown to inhibit osteoblastic bone formation through upregulation of Smurf 1 and 2 (99). In addition, Smurfs are responsible for the translocation of I-Smads from the nucleus into the cytoplasm, and enhance I-Smad interaction with the type-I receptors (100). This also results in Smurf-dependent ubiquitin degradation of the type-I receptors, leading to a down-regulation of cell surface receptor expression. A Ring type E3 ligase, Arkadia induces the ubiquitination of Smad7 but not type-I receptors, leading to an amplification of TGF-β signaling (101).
NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) was recently found to be a direct binding partner of Smad7 (102). NEDD4-2 is structurally similar to Smurfs 1 and 2 (Smad ubiquitin regulatory factors). It can interact with Type I receptor via Smad 7, and induce its degradation. It can also bind to Smad 2 and 3 in the ligand-dependent manner, and degrade Smad 2, but not Smad 3. Overexpression of NEDD4-2 inhibits the transcriptional activity induced by TGF-β and BMPs. An ubiquitin C-terminal hydrolase (UCH37), is a deubiquitinating enzyme that can potentially reverse Smurf-mediated ubiquitination. It forms a stable complex with Smad 7, which deubiquitinates and stabilizes the type I TGF-β receptor (103).
4. BONE AND PREDISPOSITION OF METASTASIS TO BONE
Metastatic bone lesions are frequently occurring events in certain solid tumors, and the predominant type of metastasis in advanced diseases of breast cancer, prostate cancer and lung cancer. However it is still largely unknown, how the cancer cells (seeds) acquired capacities and predispositions, leading to the dissemination and development of bone metastasis. Recent studies from BMPs and their implication in malignancies may have shed light on this. It suggests that BMPs may play profound roles in assisting cancer cells to acquire certain capacities and preferentially disseminate towards bone.
4.1 Aberrant expression and signaling of BMPs in primary tumors and, their association with bone metastasis
BMPs and their receptors signaling have been implicated in development and progression of a variety of solid tumors, including prostate cancer, breast cancer and lung cancer etc (104, 105). Research currently focuses on BMP expression in prostate cancer and breast cancer. They are the most common malignancies with the highest incidence of bone metastasis, and are also representative for two distinct types of metastatic bone lesions; osteoblastic and osteolytic lesions.
4.1.1. Prostate cancer
An elevated level of BMP6 is associated with higher grade primary tumors and advanced prostate cancer with metastasis (106-109). BMP6 may contribute to the progression of prostate cancer independent of androgen stimulation (107, 109). In contrast to BMP6, BMP2, BMP4, BMP7, BMP9, BMP10 and GDF15 are expressed predominantly in normal prostate tissues, and their expression appear to be down-regulated or suppressed during the development and progression of prostate cancer (110-115).
The expression of BMPRIA, BMPRIB, and BMPRII in human prostate cancer tissues has also been investigated and was found to correlate with tumor grade. Using immunohistochemistry and Western blot analysis, it was shown that there was frequent loss of expression of these three receptors in high-grade prostate cancer. However, it appears that only the loss of expression of BMPRII has a correlation with poor prognosis in prostate cancer patients (116, 117). Loss of the expression of BMPR-IA, BMPR-IB and especially BMPR-II, in both prostate cancer tissues and cancer cell lines, has been shown to have an association with the progression of prostate cancer (114, 116-118). Intracellular signaling molecules downstream of the BMP receptors have also been shown to have altered expression patterns in prostate cancer. The level of Smad 4 and Smad 8 in the nucleus is thought to be associated with the development of prostate cancer, and loss of Smad 4 is related to progression to a more aggressive phenotype (112). The pattern of expression of BMPs may be important in the pathogenesis of osteoblastic-type metastases in prostate cancer. It suggests that aberrant phenotype and function of BMPs are implicated in tumorigenesis and progression of prostate cancer, which may provide favorable characteristics to assist cancer cells dissemination to bone.
4.1.2. Breast cancer
Reduced expression of BMPs, including BMP2, BMP4, BMP6, BMP7, BMP12, BMP15 and GDF9a, have been revealed in a breast cancer cohort using both quantitative real time PCR and immunohistochemical methods. The decreased expression of BMP2, BMP7, GDF9a and BMP15 was associated with poor prognosis of the patients (119-121). A similar reduction of these BMPs has been demonstrated in other studies (122, 123). Decreased BMP7 expression in primary tumors was associated with bone metastasis (124). In contrast to these findings, elevated expression of BMPs, such as BMP2, BMP4, BMP5 and BMP7, has been demonstrated in other studies (119, 125-128). Although the expression of specific BMPs, such as BMP2, 4, 6 and 7 in breast cancer remains controversial, the abnormalities in their expression have indicated a role in the development and progression of breast cancer.
Meanwhile, investigations into the expression patterns of BMP receptors and intracellular signaling molecules have also been conducted, but to a rather limited extent. Elevated expression of BMPR-IB was associated with high tumor grade, high tumor proliferation, cytogenetic instability, and a poor prognosis in oestrogen receptor-positive carcinomas (129). This suggests that the expression of this type I receptor may associate with the ER status, and is regulated by estrogen. The results from the host lab showed a decreased level of BMPR-1B in breast cancer, which was associated with poor prognosis (130). Activation of the Smad pathway of BMPs (Smad1/5/8) and TGF-β (Smad2) was revealed in nuclei of breast cancer cells in both primary tumors and bone metastases, and similar involvements were also seen in an in vivo model. TGF-β3 and BMP2 could promote motility and invasiveness of breast cancer cells (MDA-231-D) in vitro. Moreover, expression of domain-negative receptors for TGF-β and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-ß promote invasion and bone metastasis of breast cancer (131). Although the phenotypic profile of BMPs needs to be clarified, there is no doubt that BMP and their receptor signaling play important roles in breast cancer, particularly the disease specific bone metastasis.
4.2 BMPs affect growth and survival of cancer cells
The notion that the BMPs may play a profound role in the progression of primary prostate tumors and the development of secondary tumors, especially bone metastasis, has been supported by lines of biological based investigations. However, the precise machinery underlying this connection is still unclear. The application of recombinant human BMPs (rh-BMPs) and artificial manipulation of the expression of BMPs or the signaling molecules makes it possible to investigate the biological functions of BMPs in cancer in vitro.
4.2.1. BMP and proliferation of cancer cells
Uncontrolled proliferation is one of the predominant features for cancer cells. As other members of TGF-β family, BMPs can inhibit proliferation of cancer cells. However, certain elements could divert the responses of cancer cell to BMPs, which include expression profile of androgen receptors, estrogen receptors, BMP receptors, intracellular signaling molecules and the specific BMPs.
BMP2 and 4 inhibit the growth of the androgen-sensitive prostate cancer cell line LNCaP, but not the androgen-insensitive PC-3 (132). The inhibitory effect of BMP2/4 on cell proliferation is related to the activation of Smad 1, up-regulation of the cyclin-dependent kinase inhibitor (CDKI) p21 (CIP1/WAF1), and phosphorylation of retinoblastoma (Rb) (132). Simliar, BMP2 inhibits estrodiol-induced proliferation of breast cancer cells, via up-regulation of cyclin kinase inhibitor, p21 which in turn inhibits the estradiol-induced cyclin D1-associated kinase activity (133). The up-regulation of p21 by BMP2 can also prevent EGF-induced proliferation of breast cancer cells (MDA-MB-231) (134). It is interesting to note that the regulation of p21 expression by BMP2 was mediated by Type-I receptors, Smad-1 and Smad-4. In MDA-MB-468 which only expresses Smad-1, BMP2 fails to induce p21 and inhibits the cellular proliferation (135). On the other hand, BMP6 and BMP7, are able to inhibit the proliferation of both androgen-sensitive and androgen-insensitive prostate cancer cells. BMP6 inhibits the proliferation of both LNCaP and DU-145 cells, by up-regulation of several cyclin-dependent kinase inhibitors such as p21/CIP, p18 and p19, which can be prevented by Noggin (136). Furthermore, BMP6 and BMP7 can also inhibit both oestrogen sensitive and insensitive breast cancer cells (137, 138). In contrast to the inhibitory effect, some BMPs may indirectly promote the proliferation of breast cancer cells, such as BMP4 which has a synergetic effect on the proliferation of breast cancer cells induced by fibroblast growth factor (FGF), epidermal growth factor (EGF) and hepatocyte growth factor (HGF) (139). This contrasting effect on proliferation of breast cancer cells was clearly demonstrated in a recently published study, where BMP7 could promote proliferation of MDA-MB-231 and BT-474 cells, but showed an inhibitory effect on the other breast cancer cell lines tested (140).
The nature of the diverse, sometimes contrasting effects of different BMPs is interesting, but the underlying mechanisms remain unclear. While BMPs themselves may hold some of the answers, BMP receptors are probably also determining factors in distinguishing between the pro- or anti-proliferation effects seen in prostate cancer cells. For example, Kim et al demonstrated that transfection of a domain negative BMP-RII (BMP-RIIDN) into PC-3 cells (PC3M), resulted in a growth rate 10 time higher than that in control cells in a murine tumor model (117). Once the PC-3 cells express a constitutively active BMPRIB (c.a.-BMPRIB) in a tetracycline (Tet)-regulated manner, the Tet/doxycycline-regulated expression of the c.a.-BMPRIB results in the inhibition of both the in vitro cell proliferation and the tumor growth in vivo (141). The inhibition of prostate cancer cells mediated by BMPR-IB and BMPR-II were further evident in our recent study following knockdown of these receptors (114). However, recent studies have indicated that certain BMP receptors mediate contrasting effect in breast cancer cells. Over-expression of a domain negative BMPR-II in breast cancer cells is able to interfere with the phosphorylation of Smad-1 by BMPR-II, leading to an arrest of the cancer cells at the G1 phase of the cell cycle. This suggests that coupling between BMPs and BMPR-II has a significant role in controlling the proliferation and survival of breast cancer cells (142). A domain negative Type II TGF-β receptor (dnTbetaRII) could eliminate the anti-proliferative effect of BMP-2 in breast cancer cells by preventing the phosphorylation of Smad-1 (143). One of the Type I receptors, BMPR-IA (ALK-3) has been recently shown to be involved in the activated Smad pathway which contributes to development and progression of breast cancer at primary and secondary sites (131). While BMPR-IA and BMPR-II play positive roles for BMP induced proliferation and aggressiveness in breast cancer cells, another Type I receptor, BMPR-IB has been indicated as a negative regulator (144).
A biphasic effect on the proliferation of LNCaP can be induced by rh-BMP2 under appropriate hormonal conditions. A decrease in cell proliferation in response to rhBMP2 was elicited in the presence of an androgen, which was thought to be the result of up-regulation of BMPR-IB expression. Conversely, an increase in cell growth was seen in the absence of androgen (145). Similar biphasic effects were also revealed in LNCaP following exposure to rh-BMP7. BMP7 can also promote proliferation of LNCaP at lower concentrations (20ng/ml) in the absence of exogenous androgen, but inhibits proliferation at higher concentrations (80ng/ml) (141). It clearly indicates a possibility that sexual hormones and their receptors are able to regulate the response to BMPs.
4.3.2. BMPs and Apoptosis
Apoptosis or programmed cell death is crucial for physiological control of the cell population and regulation of tissue homeostasis. Aberration in apoptosis plays important roles during oncogenesis and subsequent progression. In addition to the pivotal role in the control of cell proliferation and growth, BMPs also play a profound role in regulating the apoptosis of cancer cells. For example, BMP4 induces apoptosis of myeloma cells through ALK3 and ALK6, BMP5 acts partially by ALK3, whereas BMP6 and BMP7 rely on ALK2 (146).
BMPs can regulate the transcription of genes in control of apoptosis via the Smad dependent pathway. For example, BMP9 induces prostate apoptosis response-4 (Par4) in prostate cancer cells and subsequently leads to apoptosis through Smad dependent pathway (114). The expression of the apoptosis mediators DRP-1 death kinase and ZIP kinase may be regulated by BMPs through the Type I receptor, as demonstrated by expressing constitutively active BMP type I receptors in the cells (147). Senescent cells, as the result of BMP4 treatment had lower ERK activation, VEGF expression, and Bcl2 expression than wild-type cells (148).
BMPs can also alter apoptosis through Smad independent pathways. BMP2 activates the p38 mitogen-activated protein kinase (MAPK) pathway in medulloblastoma cells leading to apoptosis, which can be prevented by Noggin (149). BMP10, a close member to BMP9 within the superfamily, has been shown to induce apoptosis in prostate cancer cell but contrastingly through Smad independent activation of MAPK pathway (115). Additionally, BMPs themselves may mediate apoptotic effect by other factors. For example, GDF-15 is indispensable for the pro-apoptotic activity of several apoptosis-inducing agents including the retinoid-related molecules (CD437 and ST1926) (150).
The apoptotic response to BMPs is dependent upon cell type and, within the same cell type, is dependent on phenotype, hormone and growth factors status, and survival condition. For example, BMP4 can inhibit DNA synthesis and induce apoptosis in two IL-6 dependent myeloma cells (OH-2 and IH-1), but not the IL-6 independent ANBL-6 cells (151). BMP7 can stablize the level of survivin in prostate cancer cells (LNCaP and C4-2B), and restore the activity of c-jun NH2-terminal kinase (JNK), both of which contribute to the anti-apoptotic activity of BMP7 (152, 153) BMP2 partially prevents an increase in caspase-3 mRNA levels in MCF-7 cells as a result of serum withdrawal in cell culture (serum free culture condition) (154).
Most interestingly, BMPs may have biphasic effects on apoptosis in cancer cells depending on their survival condition. For example, under routine culture conditions, BMP2 showed a pro-apoptotic effect in breast cancer cells (MCF-7) through regulating the expression and function of apoptosis related genes, such as protein kinase R (PKR) and eIF2α (155). Under deprivation of serum, BMP2 increases the resistance of MCF-7 cells to hypoxia induced apoptosis, via the activation of both the MAPK pathway and ID-1, and suppression of Caspase-3 (126, 154). The other example is BMP6, which can inhibit the proliferation of breast cancer cells (MDA-MB-231). Under deprivation of serum, BMP6 turns to protect these cancer cells from stress induced apoptosis through up-regulation of survivin via the Smad dependent pathway, and activation of p38 via the Smad independent pathway (137).
4.3. Epithelial-mesenchymal transition (EMT) and aggressive phenotypes acquired by metastatic cancer cells before dissemination from primary tumors
The most predominant characteristics acquired by cancer cells are invasiveness and motility, being fundamental for their dissemination and metastasis. Epithelial to mesenchymal transition (EMT) is a process involving a sequence of changes in gene-expression patterns during which epithelial cells dissipate their epithelial features and acquire characteristics typical of mesenchymal cells. The key changes during EMT include a loss of E-cadherin expression and increases in N-cadherin, SNAI1, SLUG (SNAI2), TWIST, vimentin, fibronectin and accordingly many of these molecules have been shown to be deregulated in cancer (156). EMT has been shown to play an important role during tumor progression, leading to enhanced motile and adhesive capacities of cancer cells, and assisting them to spread and metastasize.
4.3.1. BMP and EMT
EMT regulated by BMPs has been implicated in foetal and postnatal development of different organs and tissues, and certain pathological processes including cancer. In normal development, BMP2 acts synergistically with TGF-β3 in the initiation of EMT during the generation of the endocardial cushion (157). The application of the BMP antagonist, Noggin, disrupts the EMT induced by BMPs during the development of the chicken heart (158). The EMT induced by BMP7 contributes to the repair of tubular injury in a fibrotic kidney (159, 160).
EMT not only causes a disruption of epithelial homeostasis which may lead to carcinogenesis, it can also transform the indolent tumor cells into a more aggressive colony, leading to metastasis. BMP4 can subvert the ability of mammary epithelial cells to form polarized lumen-containing structures, and also endows them with invasive properties (161). This supports the involvement of this BMP cytokine in the progression of breast cancer. In the bone metastasis-derived PC-3 prostate cancer cell line, BMP7 has been shown to induce epithelial-mesenchymal transdifferentiation with classical changes in morphology, and promote both motility and invasiveness in prostate cancer cells (152). However, in mammary epithelial cells (NMuMG), BMP7 was not able to induce EMT whereas TGF-β1 could (162). In contrast, some BMPs are able to reverse EMT and reduce the aggressive properties of tumor cells. For example, BMP6 restores E-cadherin-mediated cell-to-cell adhesion and prevents breast cancer metastasis through the down-regulation of δEF1. Higher level of δEF1 expression is associated with a more invasive phenotype of breast cancer cells (163). Another example is BMP7, which is able to increase cytokeratin expression and decrease vimentin in breast cancer cells in vitro and in vivo, leading to an epithelial-like phenotype (124).
Mechanisms underlying BMP induced EMT have been partially revealed recently. The induction of Inhibitor of differentiation factors (Id-1, Id-2 and Id-3), and activation of the proto-oncogene phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway by some BMPs (BMP2 and BMP7) has been implicated in BMP-induced EMT, but further exploration is required (164-166).
4.3.2. Influence of BMPs on cellular motility and invasion
Invasion and metastasis are the major causes of cancer related mortality. The motility and invasiveness of cancer cells are amongst the main determining factors regarding the metastatic spread of a tumor. Recent evidence demonstrates that BMPs also regulate cellular motility and the invasiveness of some malignant cells, including lung cancer cells (A549 and H7249), malignant melanoma cells, and breast cancer cells (MCF-7) (167-169). BMP2 may contribute to the invasiveness of tumor cells via the induction of tenascin-W in the tumor surrounding stroma. Tenascin-W belongs to a family of extracellular matrix glycoproteins. It has been shown to be highly expressed in the stroma around breast carcinoma lesions, and has been linked to the aggressiveness of tumor cells via its interaction with a α8 integrin. HC11 cells derived from normal mammary epithelium do not express α8 integrin and fail to cross tenascin-W-coated filters. However, 4T1 mammary carcinoma cells do express α8 integrin and their migration is stimulated by tenascin-W. BMP2 can induce the expression of tenasin-W through the p38 MAPK and JNK pathway. This is in clear contrast to TGF-β1, which is a potent inducer of tenascin-C (170). Finally, up-regulation of Id-1 by BMP2 may be another contributing factor in BMP2 related aggressiveness of breast cancer cells (171).
In the case of prostate cancer cells, studies have revealed that the motility and invasiveness of prostate cancer cells can be increased by the BMPs. BMP2 and BMP7 promote the migration and invasion of osteoblastic prostate cancer cells (LAPC-4 and LAPC-9) in a dose-dependent manner, but BMP4 does not have this effect (172). BMP2 and BMP6 can increase the in vitro invasive ability of the prostate cancer cell lines C4-2B and LuCaP (173). BMP2 and, to a lesser extent, BMP4 will stimulate PC-3 cell migration and invasion in a dose-dependent fashion, an effect which Noggin can subsequently inhibit (174). On the other hand, some other BMPs may have an inhibitory effect on the aggressiveness of breast cancer cells. For example, forced expression of GDF-9a in breast cancer cells could reduce their invasiveness in vitro (120). BMP9 and BMP10 have been shown to inhibit motility and invasion of prostate cancer cells (114, 115). The expression of MMP-13 could be enhanced by TGF-β, but was inhibited by BMP2 (175). However, whether this is implicated in the invasiveness of breast cancer cells is still unknown.
4.4. Regulatory factors of BMP
A diversity of BMPs expression and signaling occurs in malignancies during their development and progression, which also reflects the complexity of both regulatory machinery for BMPs and their interactions with other factors. A number of hormones and growth factors have been indicated in the network with BMPs.
4.4.1. Sexual hormones
In prostate cancer, androgens play an important part in the carcinogenesis, progression and metastasis of the disease, and controlling the level of circulating androgens constitutes the only effective therapy in advanced disease. Androgens can induce the expression of some BMPs, BMP receptors and intracellular signaling molecules. With regard to the receptors, androgens induce the expression of BMPR-IB mRNA, but not the expression of BMPR-IA and BMPR-II mRNAs in the androgen-sensitive human prostate cancer cell line LNCaP. As discussed above, rh-BMP2 induces a biphasic effect on the proliferation of LNCaP. In the presence of an androgen, there is a decrease in cell proliferation in response to rhBMP2. This is thought to be the result of up-regulation of BMPR-IB expression. Conversely, an increase in cell growth is seen in the absence of androgen. Thus, the induction of BMPR-IB expression by an androgen appears to convey an inhibition of cell proliferation in response to stimulation by BMPs (145). Turning to BMPs themselves, orchidectomy resulted in a decrease in the expression of BMP7 in a murine model and administration of testosterone or dihydrotestosterone caused an increase in the expression level (176). However, androgen deprivation appears to have no effect on BMP6 production in the normal rat prostate, suggesting an alternative and androgen-independent gene regulation for this particular protein (107).
The aberrations in the BMP phenotype and signaling in breast cancer may due to the ER status and self-adjustment by tumor cells themselves according to the needs for development and progression at different stages. Epigenetic regulation of BMPs and BMP receptors in breast cancer is associated with the ER status (177). Oestrogen can repress the expression of some BMP receptors, such as BMPR-IA, BMPR-IB, ACVR2A, and ACVR2B, but has no effect on the expression of ACVR1 and BMPR-II (138). In line with this observation, the expression of some BMPs and BMP receptors in breast cancer tissues has been shown to correlate with ER status. The expression of BMP7 has been found to highly correlate with the expression level of both estrogen receptor (ER) and progesterone receptor (178). Hypermethylation of BMP6 was observed in ER negative cases, indicating that BMP6 promoter methylation status correlated with ER status in breast cancer (177). Anti-oestrogen reagent raloxifene could increase the activity of the BMP4 promoter in U-2 OS osteoblast-like cells. ER-α, but not ER- β is thought to be indispensable for this effect on the BMP4 promoter. However, ER-β may synergetically enhance this activation of the BMP4 promoter by raloxifene (179). The role played by ER-β in the regulation of BMPs and BMP signaling by oestrogen in breast cancer cells remains unclear. In addition, oestrogen and BMPs can influence each other's function through interaction between their receptor and downstream signaling, such as ER and Smads (180, 181). However, the interaction between the oestrogen signaling pathway and the BMP pathway, and their implication in breast cancer still needs more exploration.
4.4.2 DNA methylation
Epigenetic regulation of genes has been involved in oncogenesis and disease progression. In term of BMPs, hypermethylation of BMP6 and thus reduced expression were observed in ER negative breast cancer tissues (177). Hypermethylation of the BMP and activin membrane-bound inhibitor (BAMBI) promoter lead to a decreased expression of the BAMBI gene, which resulted in an enhanced responsiveness to BMP signaling and thus the abnormal bone formation. (182). During cancer progression, besides the known inactivation of tumor suppressor genes by hypermethylation, activation of BMP6 by selective demethylation occurs and may also contribute to the shift to a more aggressive phenotype in prostate cancer (109). Aberrant methylation of BMP2 has also been recorded, and the resultant loss of BMP2 expression has been implicated in the carcinogenesis of gastric tumors (183).
4.4.3. Others
Several other factors and pathways have been indicated in the regulation of BMP expression and function. Nacamuli et al demonstrated that BMP3 expression can be controlled by recombinant human fibroblast growth factor in calvarial osteoblasts (184). EGF can also influence BMP expression. The expression of BMP6 has been shown to be reduced in breast cancer tissues, a reduction accompanied by a concurrent reduction in EGF receptor expression. The relation between BMP6 expression and EGF was further confirmed by the inductive expression of BMP6 in breast cancer cells (MCF-7) in vitro by EGF through EGF receptor activation (122). Retinoid induces expression of BMP2 in the retinoid-sensitive cell lines (149), and Rapamycin induced BMP4, and reduced follistatin expression in PC3 cells, which contributes to its anticancer effect (185). Our recent studies demonstrated that hepatocyte growth factor (HGF), a key regulator of metastasis and angiogenesis, could up-regulate the expression of BMP7 and BMP receptors in prostate cancer cells. This effect can be blocked by NK4, an antagonist of HGF (186, 187). It suggests that HGF participates in the change of BMP expression profile during the disease progression and metastasis. These studies collectively indicate that BMPs together with other growth factors, have a potential role to play during the development and progression of cancer, particularly in the disease specific bone metastases.
5. BMP AND COLONIZATION OF METASTATIC CANCER CELLS IN BONE
Following dissemination to bone through blood circulation, metastatic cancer cells need to survive and colonize with in bone tissue before fully establishing a metastatic lesion. During the colonisation, interactions amongst cancer cells, bone cells and bone matrix constitute a "vicious cycle" in favour of developing a bone metastasis (188-190). Within the vicious cycle, osteoinductive factors and osteolytic factors derived from cancer cells can act on osteoblasts and osteoclasts or their respective progenitor cells to stimulate their differentiation and function (Table 3), leading to corresponding osteoblastic and osteolytic lesions. The reciprocal promotions between osteoblasts and osteoclasts will occur after initial stimulation by tumor-derived factors, which can in turn to promote colonisation of metastatic cancer cells and their subsequent development. In addition, bone matrix provides a fertile 'soil' to cancer cells, which is enriched with growth factors and NCPs. These factors also help cancer cells to survive and proliferate in the bone microenvironment (Figure 4).
5.1. Tumor cell derived osteoblastic factors
Bone metastasis has been characterised as either osteolytic or osteoblastic. This classification actually represents two extremes of a continuum in which dysregulation of the normal bone remodeling process occurs. Patients can have both osteolytic and osteoblastic metastasis or mixed lesions containing both elements. Most metastatic bone tumors from breast cancer have predominantly osteolytic lesions. In contrast, the metastatic lesions from prostate cancer are predominantly osteoblastic. During osteoblastic bone metastases, the balance between bone resorption and bone formation is tipped in favour of the latter. A number of factors produced by cancer cells, such as platelet-derived growth factor (PDGF), insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), VEGF, Wingless and NT-1 (WNT1), parathyroid hornone related protein (PTHrP), urokinase-type plasminogen activator (uPA), prostate specific antigen (PSA), endothelin-1 (ET-1) and BMPs, have been implicated in osteoblastic lesions. These osteoblastic factors can either promote proliferation and function of osteoblasts, or induce osteoblast differentiation. BMPs, being the most potent to induce bone formation, their functions have been mainly discussed in this review. In following paragraphs, we focus on discussing other osteoblastic factors.
ET-1 is a well known vasoconstrictor, and also a mitogenic factor for osteoblasts (191). Serum level of ET-1 has been shown to be increased in patients with bone osteoblastic lesions (192). In advanced prostate cancer, its expression tends to be elevated in an androgen-independent manner (193). ET-1 mediates its effects on bone formation through the Endothelin A receptor (ETAR). An ETAR antagonist (atrasentan) has been shown to prevent osteoblastic bone metastases in a mouse model and reduce skeletal morbidity in men with bone metastases from prostate cancer (194, 195). Evidence also indicates that ET-1 increases osteoblast proliferation and new bone formation by activating the Wnt signaling pathway through suppression of the Wnt pathway inhibitor DKK1(196). In addition to directly affecting osteoblasts, ET-1 can also increase prostate cancer cell proliferation and enhance the mitogenic effect of other growth factors, including IGF-I, PDGF and EGF (197).
PDGF consists of subunit A and subunit B, which form AA, BB and AB isoforms. The BB isoform is a potent osteoinductive factor, which contributes to the osteoblastic lesions through promoting the migration and proliferation of osteoblasts (198, 199). Both acidic FGF (FGF-1) and basic FGF (FGF-2) increase the proliferation of osteoblasts, while FGF-2 is able to suppress the formation of osteoclasts (200). IGF system consists of two ligands, IGF-I and IGF-II, two receptors and seven binding proteins (IGFBPs). IGFs can elicit mitogenic stimulation of osteoblasts, increase bone matrix apposition and decrease the degradation of collagen. The osteoblast-stimulating factor, IGF-I has been implicated in the formation of metastasis from prostate cancer (201). Plasma IGFBP-3 levels were lowest in patients with bone metastases, while IGFBP-2 levels were elevated in prostate cancer patients (202, 203). Although high IGF-I levels and low IGFBP-3 levels may predict the risk of developing advanced-stage prostate cancer (203), evidence indicated that IGF-I was neither necessary nor sufficient for the osteoblastic response to the metastases of prostate cancer (204). The role of IGF system in bone metastasis still requires further investigation. VEGF has been shown to promote bone formation through directly activating the osteoblasts, and facilitating angiogenesis thus indirectly stimulating the process (205-207). The elevated level of VEGF has been implicated in the development of bone metastasis in prostate cancer (208-210).
WNT1 was elevated in the prostate cancer cells of advanced metastatic prostate carcinoma (211). Wnts produced by prostate cancer cells act in a paracrine fashion to induce osteoblastic activity in the bone metastases (212). WNT signaling can be inhibited by its WNT antagonist DKK1 (213). Inhibition of WNT signaling in osteoblasts can suppress osteoblast function and result in the osteolytic phenotype. DKK-1 production occurs early in the development of skeletal metastases, which results in the masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastasis progresses, DKK-1 expression is decreased, thus allowing unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site (212).
PTHrP is an osteolytic factor, which has also been found to be abundant in bone metastases of prostate cancer. However, even in a metastatic tumor in which PTHrP is highly expressed, the osteoblastic lesions remain predominant. The explanation for this paradox is that NH2-terminal fragments of PTHrP share strong sequence homology with ET-1 and thus stimulate new bone formation by activating the ETAR (214). The osteoblastic fragments of PTHrPs are products of the cleavage of PTHrPs by prostate-specific antigen (PSA). This provides a partial molecular explanation for the osteoblastic phenotype of PTHrP-positive prostate cancer bone metastases (215). uPA is also implicated in osteoblastic bone metastasis. uPA produced by prostate cancer cells has been shown to increase the osteoblastic bone metastases (216, 217). uPA can cleave and activate TGF-β which is produced in a latent form by osteoblasts. TGF-β regulates osteoblast and osteoclast differentiation but also regulates the growth of tumor cells themselves. uPA stimulated osteoblast proliferation may also due to the hydrolysing IGF-binding proteins and resulting increased level of free IGF (218). PSA is a kallikrein serine protease, which is secreted by prostate cancer cells and used routinely as a marker of prostate cancer progression. PSA not only can cleave PTHrP to release osteoblastic PTHrP fragments, it also activates osteoblast growth factors such as TGF-β (219). Like uPA, PSA can also cleave IGFBP3, thereby IGF-I is able to bind to its receptor and stimulate osteoblast proliferation (220, 221).
MDA-BF-1 is a secreted form of the ErbB3 growth factor receptor (222). Expression of MDA-BF-1 has been shown in the prostate cancer cells of bone metastases, but not in cancer cells from primary tumors of patients with localised disease (i.e., PCa confined to the prostate). Moreover, expression of MDA-BF-1 was not found in prostate cancer cells that metastasised to the liver, adrenal glands, or lungs. (223). It has been demonstrated that MDA-BF-1 mediated specific interactions between prostate cancer cells and bone and assisted in the osteoblast-mediated progression of the cancer in bone (189).
5.2. Osteolytic factors secreted from metastatic cancer cells
Osteolytic metastasis occurs in solid tumors including breast cancer, lung cancer, and renal cancer. In addition, multiple myeloma typically causes extensive bone destruction (224). The dominant feastures of osteolytic metastasis are lytic and destructive, although local bone formation response can also be observed. Most in vivo studies indicate that osteolysis is caused by osteoclast stimulation, not by the direct effects of cancer cells on bone. Osteolytic metastases are associated with increased osteoclast activity and reduced osteoblast activity. Metastatic cancer cells produce factors that stimulate osteoclastic bone resorption directly or indirectly. These factors include PTHrP, IL-1, IL-6, prostaglandin E2, TNF, and CSF-1.
PTHrP is one of the major mediators secreted by cancer cells which can induce osteolytic bone metastasis (2, 224). Expression of PTHrP in primary tumors of breast cancer are highly associated with bone metastases (225). These clinical observations have been confirmed by using a mouse model in which monoclonal antibodies directed against the 1-34 region of PTH-rP dramatically reduced the development and progression of bone metastasis (11). PTH-rP produced in breast cancer cells does not directly activate osteoclasts. It binds with PTH receptor on stromal cells/osteoblasts and increases the production of receptor activator of nuclear factor κB ligand (RANKL) that plays a central role in osteoclast differentiation and activation. RANKL then interacts with RANK expressed in the hematopoietic osteoclast precursors and promotes these precursors to differentiate into mature osteoclasts (226).
IL-6 is a potent stimulator of osteoclast formation and can enhance the effects of PTHrP on osteoclasts (227, 228). IL-6 is constitutively expressed by renal, bladder, prostate, cervical, glioblastoma and breast carcinoma cells (229-232).
Metastatic cancer cells may also produce IL-1, TNF and prostaglandins which increase RANKL expression and stimulate osteoclasts (233, 234). A recent study showed that breast cancer cells could stimulate osteoclastogenesis and prolong osteoclast survival by expressing and secreting CSF-1 (235, 236).
5.3. Abundant deposition of growth factors and molecules in bone contributes to the vicious circle
The question of why the bone is the most preferred metastatic site of prostate cancer has aroused intense interest for investigation. One would first contemplate the specific shortcut of blood circulation from primary sites to bone. For instance, a rich venous plexus surrounds the prostate and connects to the venous drainage of the spine: this collection of veins (Batson's plexus) is potentially one of the reasons why the lumbosacral spinal metastases are common in advanced prostate cancer (237). However, the anatomical explanation is not able to explain why the other axial skeleton, skull and ribs may also be involved in the bone metastasis from prostate cancer. A fertile 'soil' provided by bone on the other hand, may give some answer to the question why 'seeds' metastasise to bone.
The bone matrix synthesized by osteoblasts has a particular abundance of cytokines and non-collagen proteins, which may attract prostate cancer cells and allow them to survive and proliferate in the bone matrix. For example, BMPs and TGF-β enriched in bone matrix can facilitate the development of bone metatstasis. Osteonectin, osteopontin, osteocalcin, and bone sialoprotein can also modulate the properties of prostate cancer cells and facilitate their spreading and growth, including promoting their migration, invasion and proliferation (238-243).
Noncollagenous proteins (NCPs) released or synthesized through bone resorption and bone formation also help to generate a fertile 'soil'. NCPs include fibronectin, osteonectin, thrombospondin-2, βig-h3, bone gla protein (BGP, or osteocalcin), matrix gla protein (MGP), Small Integrin-Binding Ligand N-linked Glycoproteins (SIBLINGS) and small bone proteoglycans. One of the most abundant NCPs in bone matrix is fibronectin, which is accumulated extraceullarly at sites of osteogenesis and plays a profound role in the differentiation, proliferation and survival of osteoblasts (244-246). Osteonectin ('bone connector') was initially called 'bone-specific nucleator' of mineralization as it has high affinity for both collagen and mineral (247). It has been subsequently found to be present throughout the body, particularly at sites of tissue remodelling and matrix assembly. Evidence suggests that it is crucial in maintaining the bone turnover (248). Thrombospondin-2 is also abundant in bone, which may promote bone resorption and inhibit the bone formation through negatively controling the differentiation of bone cell precursors (249-251). Another abundant NCP βig-h3, which is induced by TGF-β, inhibits the differentiation of osteoblasts through interaction with the integrins αVβ3 and αVβ5 (252, 253). Osteocalcin may inhibit bone formation (254), while MGP is a powerful inhibitor of mineralisation in arteries and cartilage (255). Members of the SIBLINGS family include: bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein (DMP), dentin sialophosphoprotein (DSPP) and matrix extracellular protein (MEPE). BSP has been suggested to be involved in hydroxyapatite nucleation (256), and to promote adhesion, differentiation and some other biological functions of osteoclasts (257). Osteopontin is crucially involved in anchoring osteoclasts to the mineral matrix of bone surface via the integrin αVβ3 (258, 259). Osteopontin is required and probably indispensable during the process of bone resorption (260, 261). Nine of 12 known Small Leucine-Rich Proteoglyans (SLRPs) have been found in skeletal tissue (262). The best characterized SLRP in bone is biglycan, which plays an important role in the differentiation of osteoblast precursors (263). It is also involved in the osteoblasts differentiation induced by BMP2/4 (264, 265).
Above all, both osteoblastic and osteolytic activities are indispensable for all types of bone metastases. In patients with osteoblastic lesions from prostate cancer, blood and urinary levels of bone resorption markers are often elevated (266). Blocking osteoclastic bone resorption can reduce related skeletal events in prostate cancer patients (267). Both osteoblasts and osteoclasts cooperate to drive the settlement and growth of cancer cells in bone.
5.4. Pivotal role of BMPs in bone metastasis
BMPs are the most powerful bone inductive factors enriched in bone matrix (97). BMPs are not only synthesised by osteoblasts and stored in bone matrix, they can also be secreted by cancer cells. BMPs secreted from the cancer cells can enhance their aggressiveness and also act on bone cells resulting bone lesions, in addition BMP released from bone matrix following abnormal osteolytic activities can act to coordinate the mutual reactions between cancer cells and bone environments. BMPs can also help to establish new blood vasculature in support of colonization and development of bone metastasis (Figure 5). BMPs are a group of key factors involved in the 'vicious circle' of bone metastasis.
5.4.1. Adaptable expression of BMPs in bone metastases
The aberrant expression of BMPs in cancer has been implicated in the progression of the disease. Primary prostate tumors and metastatic prostate tumors have a different phenotypic pattern of BMP expression and adopt different signaling pathways downstream of the BMP receptor. Most BMPs and BMP receptors are detectable at a relatively high level in normal prostate tissue. Their expression decreases in a manner that correlates with progression of the primary tumor, except BMP6 which shows an increase in this case. The expression of BMP7, GDF15 and BMPR-IB can be induced by exposure to androgens in the androgen-sensitive prostate cancer cell lines and the 'normal' prostate epithelial cell lines. The same androgen inducible effects were not seen with BMP6 (109, 145, 176, 268). Aberrant expression of BMPs and BMP-associated molecules have also been shown to have a prognostic value (117). The pattern of BMP expression has a clear and close relationship with the development and progression of primary prostate tumors and also contributes to the onset and development of bone metastases. For example, BMP6 remains highly expressed in both primary prostate tumors and metastatic bone lesions. In contrast, BMP7 and GDF15, which are expressed at low levels in normal prostate and in primary prostate tumors, are re-expressed at a high level in skeletal metastatic lesions. This re-expression in metastatic bone lesion can be seen at a higher level than that seen in the normal bone tissues around the metastatic lesions (111, 269). BMPs that are normally enriched in the bone environment, not only promote the motility and invasion of cancer cells, they are also able to induce the expression of other growth factors, which enhances the vicious circle of bone-tumor-bone interactions. A few links have been documented in recent years. For example, BMP2 is able to stimulate a 2.7-fold increase in osteoprotegerin (OPG) expression in PC-3 cells which inhibits osteoclastogenesis (132), and BMP7 induces VEGF protein and mRNA expression in C4-2B cells, which contributes to the pro-osteoblastic activity of C4-2B cells. CM from breast cancer cells (MCF-7) or prostate cancer cells (LNCaP) could up-regulate osteopontin (OPN) in osteoblasts through the protein kinase C (PKC) pathway and mitogen-activated protein kinase (MAPK) pathway. This resulted in inhibition of proliferation and differentiation in osteoblastic cells (270).
From the moment a metastatic cell settles in the bone, there is constant interaction between the tumor cell and its residing microenvironment. Host factors from the bone environment and factors generated by the cancer cell exhibit a reciprocal influence over each other, the BMPs secreted by the cancer cells would certainly influence remodeling of the bone, including osteoblastic and osteoclastic activity. However, it remains unclear as to how exactly the local factors participate in the regulation of BMP expression in the prostate cancer cells. The aforementioned factors, such as sexual hormones, EGF and HGF may play a role in this reciprocal regulation and adaptable expression of BMPs in bone metastases.
5.4.2. BMPs and Angiogenesis
Angiogenesis is an important event during the development and progression of both primary and secondary tumors. In order for tumors to grow beyond a minute size, they need to induce the formation of new blood vessels (a process known as neovascularisation). In order for them to do this they need to promote angiogenesis, which has an activation phase where the endothelial cells proliferate and migrate, and a late phase where the cells stop migrating, and stabilisation and maturation of the blood vessel occurs. It has been suggested that TGF-β1 signaling via ALK1/Smad1/-5 induced the activation phase of angiogenesis whereas TGF-β1 via ALK5/Smad2/-3 is responsible for promoting the late phase (271). Culturing on type-I collagen can promote spontaneous formation of tubular structures by endothelial cells, via up-regulated levels of BMPR-IB and BMPR-II expression. BMPR-II expression has been shown to be involved in the differentiation of endothelial cells, and suggested that the BMPRs, especially BMPR-II, may play a role during angiogenesis, and hence may be altered in human cancers (272). Smads are the transcriptional regulators of BMP target genes, including VEGF. Smad3 expression in rat proximal tubular cells resulted in an induction of endothelial cell proliferation, and an up-regulation of VEGF-A, while Smad2 induced expression of thrombospondin-1, suggesting that these two Smads have opposing roles during angiogenesis (273). In gastric cancer cells, Smad3 results in a down-regulation of VEGF expression, and smaller tumor nodules with decreased blood vessel formation (274). Unlike Smad2 and Samd3, Smad4 overexpression in pancreatic carcinomas can result in both decreased VEGF expression and an up-regulation of thrombospondin-1, leading to an inhibition of angiogenesis (275).
In addition to the direct stimulation of the aggressiveness of prostate cancer cells, some BMPs including BMP2, 4, 6, 7 and GDF5, are capable of inducing angiogenesis. This may be one of the ways in which they contribute to the process of bone formation (276-279). BMPs can not only directly regulate proliferation and migration of vascular endothelial cells, they can also promote angiogenesis indirectly through up-regulation of the expression of VEGF in both cancer cells and osteoblasts. Noggin, the BMP antagonist, produces the same effect as anti-VEGF antibody: it diminishes the pro-osteoblastic activity of osteoblast cells which are induced by conditioned medium from C4-2B cells (208, 278, 280). Also, the early stage of bone induction by rhBMP2 can be blocked by the anti-angiogenic agent (TNP-470) (277). This evidence indicates that the control of angiogenesis is, to some extent, integrated with the influence which BMPs have over osteoblastic activity. Dai et al have demonstrated that it is possible for BMP7 to promote osteosclerosis through VEGF in the skeletal metastases from prostate cancer (208). This angiogenesis induced by BMPs can also be synergized by basic fibroblast growth factor (bFGF) and TGF-β1(281), which suggests that the angiogenesis induced by BMPs is a vital event during the initial stage of bone metastasis development. In contrast to TGF-β1 and most BMPs, BMP9 has been shown to inhibit the proliferation of endothelial cells, as well as block VEGF mediated angiogenesis, via ALK-1 and BMPR-II and downstream Smad1/5 signaling (282).
5.4.3. Therapeutic potential of targeting BMPs
Both clinical and experimental studies suggest profound potential for targeting BMPs in treating bone metastasis. Decreased expression of BMP7 has been indicated in primary tumors in association with bone metastases. BMP7 is able to inhibit the growth of breast cancer tumors at primary sites and in bone in vivo (124). Orthotropic implant of tumors with silk scaffolds which were coupled with bone morphogenetic protein-2 (BMP2), and seeded with bone marrow stromal cells (BMSC), contributed to metastatic spread of breast cancer cells (283). These studies suggest that BMPs are involved in the bone metastasis of breast cancer. On the other hand, lack of BMP antagonists in breast cancer may contribute to the osteoblastic lesions of breast cancer. Conditioned medium (CM) from breast cancer cells (HT-39) could result in an up-regulation of bone sialoprotein mRNA expression in osteoprogenitor cells (MC3T3-E1 cells), and a promotion of their osteoblastic behaviour. This effect could be blocked through the addition of Noggin, a BMP antagonist (284). A more recent study also demonstrated that lack of Noggin expression in both breast and prostate cancer cells was associated with osteoblastic activities in bone metastases. Forced expression of Noggin in an osteo-inductive prostate cancer cell line (C4-2B) reduced in vivo osteoblastic responses induced by its intravenous xenografts, but had little or no influence on bone resorption and tumor growth (285). Unlike Noggin, another BMP antagonist, Gremlin, has been demonstrated to be over-expressed in some human cancers, including breast cancer (286). However, the roles that Gremlin and other BMP antagonists play in coordinating the osteoblastic and osteolytic activities in bone metastatic lesions are far from clear.
Meanwhile, increased expression of BMP receptors and activation of BMP signaling have also been implicated in breast cancer and the corresponding bone metastasis from the tumor. For example, BMPR-IB was up-regulated in oestrogen receptor-positive carcinomas and was associated with high tumor grade, high tumor proliferation, cytogenetic instability, and a poor prognosis (129). Activation of Smad pathway of BMPs (Smad1/5/8) and TGF-β (Smad2) was revealed in nuclei of breast cancer cells at both primary tumors and bone metastasis, an observation supported by studies using in vivo tumor models (287). Whether targeting R-Smads, using methods such as small inhibiting molecules is able to prevent bone metastasis, requires investigation.
BMPs are partly involved in the occasional osteolytic appearance in bone metastasis. The expression of BMP receptors in prostate cancer cells can also be influenced by stromal factors, such as hepatocyte growth factor (187). In an in vivo bone tumor model, exposure of tumor bearing subjects to Noggin, an antagonist of BMPs, reduces the size of bone lesions by a mechanism that involves both osteoblastic and osteolytic processes. The BMP antagonists, Noggin and follostatin, are also determining factors to the cells response to BMPs. Interestingly, the expression of these antagonists can be regulated by BMPs themselves probably through an autocrine or paracrine feedback loop. A good example is BMP7, whose endogenous expression is intimately linked to the levels of Noggin and follistatin in the same cell (288). These findings collectively indicate the value of BMPs and their antagonists in the management of bone metastasis, and also highlight the complexity of the network which has to be clarified in future study.
6. CONCLUSIONS AND PERSPECTIVE
Aberrant expression of BMPs and BMP signaling molecules has been implicated in a variety of solid tumors and disease specific bone metastasis. The phenotypic profile of BMPs, BMP receptors and intracellular signaling molecules can be modified by sexual hormone and growth factors, in order to coordinate biological behaviors of cancer cells during the disease progression. Most BMPs elicit inhibitory effects on proliferation of cancer cells through their receptor signaling. At the primary site, expression of these BMPs is suppressed by hypermethylation or acquired growth independent of sexual hormone, which allows the corresponding cancer cells to grow and progress under reduced influence by the BMPs, such as BMP2, BMP4, BMP7, BMP9 and BMP10. Meanwhile expression of some BMPs, including BMP6 and BMP7, are up-regulated and are implicated in the EMT and enhanced cell invasion and motility, leading to a more aggressive phenotype and subsequent dissemination to secondary sites. This adaptable expression profile of BMPs may also occur in bone metastases, such as re-expression of BMP7 by prostate cancer cells assisting colonization of the cancer cells in bone. Involvement of BMP receptor signallling has also been clearly indicated in the bone metastases, particularly from prostate cancer and breast cancer. BMPs not only directly act on cancer cells to coordinate their abilities during disease progression and bone metastasis, they also indirectly contribute to bone metastasis through regulating tumor related angiogenesis. Together with osteoblastic factors, osteolytic factors, and bone microenvironment, BMPs and their receptors signaling form a vicious circle during bone metastasis.
More recent studies have demonstrated activation of BMP signaling in both breast primary tumors and bone metastases, which contribute to aggressiveness of tumor cells, and development of bone lesions. Lack of Noggin in both breast and prostate cancer cells correlates with their active osteoblastic feature. In the in vivo bone tumor model, Noggin, an antagonist of BMPs, has been shown to prevent bone metastasis by inhibiting both osteoblastic and osteolytic processes. These findings collectively indicate a promising therapeutic value for BMPs and their antagonists in the management of bone metastases.
In conclusions, BMPs and their signaling pathways play critical roles in the development, progression, and metastasis of various cancers. The protein and the receptors present important prognostic and therapeutic opportunities in cancers. Further investigations to elucidate the mechanisms underlying the involvement of BMPs in cancer are necessary, as is exploration on the therapeutic potential of these new targets.
7. ACKNOWLEDGMENTS
The authors would thanks Cancer Research Wales for their support. The authors also thank Sevier Medical Art for their kind permission to produce some of present figures using their prepared images.
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8. REFERENCES
1. K.R. Hess, G.R. Varadhachary, S.H. Taylor, W. Wei, M.N. Raber, R. Lenzi, and J.L. Abbruzzese: Metastatic patterns in adenocarcinoma. Cancer 106, 1624-1633 (2006) 91. Y. Yoshida, S. Tanaka, H. Umemori, O. Minowa, M. Usui, N. Ikematsu, E. Hosoda, T. Imamura, J. Kuno, T. Yamashita, K. Miyazono, M. Noda, T. Noda, and T. Yamamoto: Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103, 1085-1097 (2000) 136. D.R. Haudenschild, S.M. Palmer, T.A. Moseley, Z. You, and A.H. Reddi: Bone morphogenetic protein (BMP)-6 signaling and BMP antagonist noggin in prostate cancer. Cancer Res 64, 8276-8284 (2004) 181. L. Wu, Y. Wu, B. Gathings, M. Wan, X. Li, W. Grizzle, Z. Liu, C. Lu, Z. Mao, and X. Cao: Smad4 as a transcription corepressor for estrogen receptor alpha. J Biol Chem 278, 15192-15200 (2003) 226. R.J. Thomas, T.A. Guise, J.J. Yin, J. Elliott, N.J. Horwood, T.J. Martin, and M.T. Gillespie: Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140, 4451-4458 (1999) 271. M.J. Goumans, G. Valdimarsdottir, S. Itoh, A. Rosendahl, P. Sideras, and P. ten Dijke: Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 21, 1743-1753 (2002) 301. T. Ebisawa, K. Tada, I. Kitajima, K. Tojo, T.K. Sampath, M. Kawabata, K. Miyazono, and T. Imamura: Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J Cell Sci 112 (Pt 20), 3519-3527 (1999) 320. A.C. McPherron and S.J. Lee: GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. J Biol Chem 268, 3444-3449 (1993) Key Words: Bone morphogenetic protein, BMP, Smad, Bone Metastasis, Review
Send correspondence to: Lin Ye, Metastasis an Angiogenesis Research Group, Department of Surgery,Cardiff University School of Medicine, Cardiff, CF14 4XN, UK, Tel: 004402920742893, Fax: 004402920742896, E-mail:yel@cf.ac.uk
doi:10.1002/cncr.21778
2. G.R. Mundy: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2, 584-593 (2002)
doi:10.1038/nrc867
3. A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M.J. Thun: Cancer statistics, 2009. CA Cancer J Clin 59, 225-249 (2009)
doi:10.3322/caac.20006
4. M.P. Roudier, C. Morrissey, L.D. True, C.S. Higano, R.L. Vessella, and S.M. Ott: Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol 180, 1154-1160 (2008)
doi:10.1016/j.juro.2008.04.140
5. Y. Du, I. Cullum, T.M. Illidge, and P.J. Ell: Fusion of metabolic function and morphology: sequential (18F)fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin Oncol 25, 3440-3447 (2007)
doi:10.1200/JCO.2007.11.2854
6. M.S. Bendre, A.G. Margulies, B. Walser, N.S. Akel, S. Bhattacharrya, R.A. Skinner, F. Swain, V. Ramani, K.S. Mohammad, L.L. Wessner, A. Martinez, T.A. Guise, J.M. Chirgwin, D. Gaddy, and L.J. Suva: Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 65, 11001-11009 (2005)
doi:10.1158/0008-5472.CAN-05-2630
7. S.M. Kakonen, K.S. Selander, J.M. Chirgwin, J.J. Yin, S. Burns, W.A. Rankin, B.G. Grubbs, M. Dallas, Y. Cui, and T.A. Guise: Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem 277, 24571-24578 (2002)
doi:10.1074/jbc.M202561200
8. J.J. Yin, K. Selander, J.M. Chirgwin, M. Dallas, B.G. Grubbs, R. Wieser, J. Massague, G.R. Mundy, and T.A. Guise: TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103, 197-206 (1999)
doi:10.1172/JCI3523
9. O. Kudo, A. Sabokbar, A. Pocock, I. Itonaga, Y. Fujikawa, and N.A. Athanasou: Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32, 1-7 (2003)
10. J.J. Yin, C.B. Pollock, and K. Kelly: Mechanisms of cancer metastasis to the bone. Cell Res 15, 57-62 (2005)
doi:10.1038/sj.cr.7290266
11. T. Yoneda and T. Hiraga: Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328, 679-687 (2005)
doi:10.1016/j.bbrc.2004.11.070
12. M.R. Urist: Bone: formation by autoinduction. Science 150, 893-899 (1965)
doi:10.1126/science.150.3698.893
13. J.M. Wozney, V. Rosen, A.J. Celeste, L.M. Mitsock, M.J. Whitters, R.W. Kriz, R.M. Hewick, and E.A. Wang: Novel regulators of bone formation: molecular clones and activities. Science 242, 1528-1534 (1988)
doi:10.1126/science.3201241
14. A.J. Celeste, J.A. Iannazzi, R.C. Taylor, R.M. Hewick, V. Rosen, E.A. Wang, and J.M. Wozney: Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone. Proc Natl Acad Sci U S A 87, 9843-9847 (1990)
doi:10.1073/pnas.87.24.9843
15. S.J. Lee: Identification of a novel member (GDF-1) of the transforming growth factor-beta superfamily. Mol Endocrinol 4, 1034-1040 (1990)
doi:10.1210/mend-4-7-1034
16. E. Ozkaynak, D.C. Rueger, E.A. Drier, C. Corbett, R.J. Ridge, T.K. Sampath, and H. Oppermann: OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. Embo J 9, 2085-2093 (1990)
17. J.M. Wozney, V. Rosen, M. Byrne, A.J. Celeste, I. Moutsatsos, and E.A. Wang: Growth factors influencing bone development. J Cell Sci Suppl 13, 149-156 (1990)
18. S.J. Butler and J. Dodd: A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons. Neuron 38, 389-401 (2003)
doi:10.1016/S0896-6273(03)00254-X
19. Y. Cui, F. Jean, G. Thomas, and J.L. Christian: BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. Embo J 17, 4735-4743 (1998)
doi:10.1093/emboj/17.16.4735
20. D.B. Constam and E.J. Robertson: Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol 144, 139-149 (1999)
doi:10.1083/jcb.144.1.139
21. A. Tsuji, E. Hashimoto, T. Ikoma, T. Taniguchi, K. Mori, M. Nagahama, and Y. Matsuda: Inactivation of proprotein convertase, PACE4, by alpha1-antitrypsin Portland (alpha1-PDX), a blocker of proteolytic activation of bone morphogenetic protein during embryogenesis: evidence that PACE4 is able to form an SDS-stable acyl intermediate with alpha1-PDX. J Biochem (Tokyo) 126, 591-603 (1999)
22. O. Hashimoto, R.K. Moore, and S. Shimasaki: Posttranslational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota. Proc Natl Acad Sci U S A 102, 5426-5431 (2005)
doi:10.1073/pnas.0409533102
23. S. Mazerbourg and A.J. Hsueh: Genomic analyses facilitate identification of receptors and signaling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands. Hum Reprod Update 12, 373-383 (2006)
doi:10.1093/humupd/dml014
24. S.J. Lee and A.C. McPherron: Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A 98, 9306-9311 (2001)
doi:10.1073/pnas.151270098
25. M.A. Brown, Q. Zhao, K.A. Baker, C. Naik, C. Chen, L. Pukac, M. Singh, T. Tsareva, Y. Parice, A. Mahoney, V. Roschke, I. Sanyal, and S. Choe: Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 280, 25111-25118 (2005)
doi:10.1074/jbc.M503328200
26. A. Aono, M. Hazama, K. Notoya, S. Taketomi, H. Yamasaki, R. Tsukuda, S. Sasaki, and Y. Fujisawa: Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer. Biochem Biophys Res Commun 210, 670-677 (1995)
doi:10.1006/bbrc.1995.1712
27. D.I. Israel, J. Nove, K.M. Kerns, R.J. Kaufman, V. Rosen, K.A. Cox, and J.M. Wozney: Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors 13, 291-300 (1996)
doi:10.3109/08977199609003229
28. A. Suzuki, E. Kaneko, J. Maeda, and N. Ueno: Mesoderm induction by BMP-4 and -7 heterodimers. Biochem Biophys Res Commun 232, 153-156 (1997)
doi:10.1006/bbrc.1997.6219
29. L. Ye, J.M. Lewis-Russell, H.G. Kyanaston, and W.G. Jiang: Bone morphogenetic proteins and their receptor signaling in prostate cancer. Histol Histopathol 22, 1129-1147 (2007)
30. J.L. Wrana, L. Attisano, R. Wieser, F. Ventura, and J. Massague: Mechanism of activation of the TGF-beta receptor. Nature 370, 341-347 (1994)
doi:10.1038/370341a0
31. L. Attisano, J.L. Wrana, F. Lopez-Casillas, and J. Massague: TGF-beta receptors and actions. Biochim Biophys Acta 1222, 71-80 (1994)
doi:10.1016/0167-4889(94)90026-4
32. J. Greenwald, W.H. Fischer, W.W. Vale, and S. Choe: Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nat Struct Biol 6, 18-22 (1999)
doi:10.1038/4887
33. T. Kirsch, W. Sebald, and M.K. Dreyer: Crystal structure of the BMP-2-BRIA ectodomain complex. Nat Struct Biol 7, 492-496 (2000)
doi:10.1038/75903
34. J.L. Wrana, H. Tran, L. Attisano, K. Arora, S.R. Childs, J. Massague, and M.B. O'Connor: Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol Cell Biol 14, 944-950 (1994)
35. P.D. Mace, J.F. Cutfield, and S.M. Cutfield: High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: implications for ligand binding. Biochem Biophys Res Commun 351, 831-838 (2006)
doi:10.1016/j.bbrc.2006.10.109
36. A. Moustakas and C.H. Heldin: From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction. Genes Dev 16, 1867-1871 (2002)
doi:10.1101/gad.1016802
37. A. Nohe, S. Hassel, M. Ehrlich, F. Neubauer, W. Sebald, Y.I. Henis, and P. Knaus: The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277, 5330-5338 (2002)
doi:10.1074/jbc.M102750200
38. A. Nohe, E. Keating, P. Knaus, and N.O. Petersen: Signal transduction of bone morphogenetic protein receptors. Cell Signal 16, 291-299 (2004)
doi:10.1016/j.cellsig.2003.08.011
39. C.H. Heldin, K. Miyazono, and P. ten Dijke: TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471 (1997)
doi:10.1038/37284
40. Y. Shi and J. Massague: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685-700 (2003)
41. M. Kretzschmar and J. Massague: SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 8, 103-111 (1998)
doi:10.1016/S0959-437X(98)80069-5
42. H. Jornvall, A. Blokzijl, P. ten Dijke, and C.F. Ibanez: The orphan receptor serine/threonine kinase ALK7 signals arrest of proliferation and morphological differentiation in a neuronal cell line. J Biol Chem 276, 5140-5146 (2001)
doi:10.1074/jbc.M005200200
43. Y.G. Chen and J. Massague: Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors. J Biol Chem 274, 3672-3677 (1999)
doi:10.1074/jbc.274.6.3672
44. L. Attisano and S.T. Lee-Hoeflich: The Smads. Genome Biol 2, REVIEWS3010 (2001)
45. W. Chen, X. Fu, and Z. Sheng: Review of current progress in the structure and function of Smad proteins. Chin Med J (Engl) 115, 446-450 (2002)
46. M. Kretzschmar, J. Doody, I. Timokhina, and J. Massague: A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev 13, 804-816 (1999)
doi:10.1101/gad.13.7.804
47. Y. Zhang, C. Chang, D.J. Gehling, A. Hemmati-Brivanlou, and R. Derynck: Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A 98, 974-979 (2001)
doi:10.1073/pnas.98.3.974
48. K. Miyazawa, M. Shinozaki, T. Hara, T. Furuya, and K. Miyazono: Two major Smad pathways in TGF-beta superfamily signaling. Genes Cells 7, 1191-1204 (2002)
doi:10.1046/j.1365-2443.2002.00599.x
49. T. Tsukazaki, T.A. Chiang, A.F. Davison, L. Attisano, and J.L. Wrana: SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95, 779-791 (1998)
50. K. Kusanagi, H. Inoue, Y. Ishidou, H.K. Mishima, M. Kawabata, and K. Miyazono: Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol Biol Cell 11, 555-565 (2000)
51. Y. Shi, Y.F. Wang, L. Jayaraman, H. Yang, J. Massague, and N.P. Pavletich: Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94, 585-594 (1998)
52. H. Shibuya, K. Yamaguchi, K. Shirakabe, A. Tonegawa, Y. Gotoh, N. Ueno, K. Irie, E. Nishida, and K. Matsumoto: TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272, 1179-1182 (1996)
doi:10.1126/science.272.5265.1179
53. K. Yamaguchi, S. Nagai, J. Ninomiya-Tsuji, M. Nishita, K. Tamai, K. Irie, N. Ueno, E. Nishida, H. Shibuya, and K. Matsumoto: XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. Embo J 18, 179-187 (1999)
doi:10.1093/emboj/18.1.179
54. K. Yamaguchi, K. Shirakabe, H. Shibuya, K. Irie, I. Oishi, N. Ueno, T. Taniguchi, E. Nishida, and K. Matsumoto: Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270, 2008-2011 (1995)
doi:10.1126/science.270.5244.2008
55. N. Kimura, R. Matsuo, H. Shibuya, K. Nakashima, and T. Taga: BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275, 17647-17652 (2000)
doi:10.1074/jbc.M908622199
56. T. Moriguchi, N. Kuroyanagi, K. Yamaguchi, Y. Gotoh, K. Irie, T. Kano, K. Shirakabe, Y. Muro, H. Shibuya, K. Matsumoto, E. Nishida, and M. Hagiwara: A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 271, 13675-13679 (1996)
doi:10.1074/jbc.271.23.13675
57. T. Ishitani, J. Ninomiya-Tsuji, S. Nagai, M. Nishita, M. Meneghini, N. Barker, M. Waterman, B. Bowerman, H. Clevers, H. Shibuya, and K. Matsumoto: The TAK1-NLK-MAPK-related pathway antagonizes signaling between beta-catenin and transcription factor TCF. Nature 399, 798-802 (1999)
doi:10.1038/21674
58. S.W. Lee, S.I. Han, H.H. Kim, and Z.H. Lee: TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB. J Biochem Mol Biol 35, 371-376 (2002)
59. K. Shirakabe, K. Yamaguchi, H. Shibuya, K. Irie, S. Matsuda, T. Moriguchi, Y. Gotoh, K. Matsumoto, and E. Nishida: TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 272, 8141-8144 (1997)
doi:10.1074/jbc.272.13.8141
60. E. Canalis, A.N. Economides, and E. Gazzerro: Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 24, 218-235 (2003)
doi:10.1210/er.2002-0023
61. Y. Re'em-Kalma, T. Lamb, and D. Frank: Competition between noggin and bone morphogenetic protein 4 activities may regulate dorsalization during Xenopus development. Proc Natl Acad Sci U S A 92, 12141-12145 (1995)
doi:10.1073/pnas.92.26.12141
62. E. Gazzerro, V. Gangji, and E. Canalis: Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J Clin Invest 102, 2106-2114 (1998)
doi:10.1172/JCI3459
63. L. Ye, J.M. Lewis-Russell, H. Kynaston, and W.G. Jiang: Endogenous bone morphogenetic protein-7 controls the motility of prostate cancer cells through regulation of bone morphogenetic protein antagonists. J Urol 178, 1086-1091 (2007)
doi:10.1016/j.juro.2007.05.003
64. D. Onichtchouk, Y.G. Chen, R. Dosch, V. Gawantka, H. Delius, J. Massague, and C. Niehrs: Silencing of TGF-beta signaling by the pseudoreceptor BAMBI. Nature 401, 480-485 (1999)
doi:10.1038/46794
65. L. Grotewold, M. Plum, R. Dildrop, T. Peters, and U. Ruther: Bambi is coexpressed with Bmp-4 during mouse embryogenesis. Mech Dev 100, 327-330 (2001)
doi:10.1016/S0925-4773(00)00524-4
66. W. Jin, C. Yun, H.S. Kim, and S.J. Kim: TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling. Cancer Res 67, 9869-9877 (2007)
doi:10.1158/0008-5472.CAN-07-0436
67. M. Sammar, S. Stricker, G.C. Schwabe, C. Sieber, A. Hartung, M. Hanke, I. Oishi, J. Pohl, Y. Minami, W. Sebald, S. Mundlos, and P. Knaus: Modulation of GDF5/BRI-b signaling through interaction with the tyrosine kinase receptor Ror2. Genes Cells 9, 1227-1238 (2004)
doi:10.1111/j.1365-2443.2004.00799.x
68. T.A. Samad, A. Rebbapragada, E. Bell, Y. Zhang, Y. Sidis, S.J. Jeong, J.A. Campagna, S. Perusini, D.A. Fabrizio, A.L. Schneyer, H.Y. Lin, A.H. Brivanlou, L. Attisano, and C.J. Woolf: DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem 280, 14122-14129 (2005)
doi:10.1074/jbc.M410034200
69. J.L. Babitt, Y. Zhang, T.A. Samad, Y. Xia, J. Tang, J.A. Campagna, A.L. Schneyer, C.J. Woolf, and H.Y. Lin: Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem 280, 29820-29827 (2005)
doi:10.1074/jbc.M503511200
70. J.L. Babitt, F.W. Huang, D.M. Wrighting, Y. Xia, Y. Sidis, T.A. Samad, J.A. Campagna, R.T. Chung, A.L. Schneyer, C.J. Woolf, N.C. Andrews, and H.Y. Lin: Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38, 531-539 (2006)
doi:10.1038/ng1777
71. R. Schwappacher, J. Weiske, E. Heining, V. Ezerski, B. Marom, Y.I. Henis, O. Huber, and P. Knaus: Novel crosstalk to BMP signaling: cGMP-dependent kinase I modulates BMP receptor and Smad activity. EMBO J 28, 1537-1550 (2009)
doi:10.1038/emboj.2009.103
72. A. Hata, G. Lagna, J. Massague, and A. Hemmati-Brivanlou: Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12, 186-197 (1998)
doi:10.1101/gad.12.2.186
73. H. Hayashi, S. Abdollah, Y. Qiu, J. Cai, Y.Y. Xu, B.W. Grinnell, M.A. Richardson, J.N. Topper, M.A. Gimbrone, Jr., J.L. Wrana, and D. Falb: The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89, 1165-1173 (1997)
74. T. Imamura, M. Takase, A. Nishihara, E. Oeda, J. Hanai, M. Kawabata, and K. Miyazono: Smad6 inhibits signaling by the TGF-beta superfamily. Nature 389, 622-626 (1997)
doi:10.1038/39355
75. M. Takase, T. Imamura, T.K. Sampath, K. Takeda, H. Ichijo, K. Miyazono, and M. Kawabata: Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem Biophys Res Commun 244, 26-29 (1998)
doi:10.1006/bbrc.1998.8200
76. A. Ishisaki, K. Yamato, S. Hashimoto, A. Nakao, K. Tamaki, K. Nonaka, P. ten Dijke, H. Sugino, and T. Nishihara: Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem 274, 13637-13642 (1999)
doi:10.1074/jbc.274.19.13637
77. F. Itoh, H. Asao, K. Sugamura, C.H. Heldin, P. ten Dijke, and S. Itoh: Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. Embo J 20, 4132-4142 (2001)
doi:10.1093/emboj/20.15.4132
78. S. Germain, M. Howell, G.M. Esslemont, and C.S. Hill: Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev 14, 435-451 (2000)
79. M. Cordenonsi, M. Montagner, M. Adorno, L. Zacchigna, G. Martello, A. Mamidi, S. Soligo, S. Dupont, and S. Piccolo: Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation. Science 315, 840-843 (2007)
doi:10.1126/science.1135961
80. K. Miyazono, S. Maeda, and T. Imamura: Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins. Oncogene 23, 4232-4237 (2004)
doi:10.1038/sj.onc.1207131
81. X.H. Feng, X. Lin, and R. Derynck: Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. EMBO J 19, 5178-5193 (2000)
doi:10.1093/emboj/19.19.5178
82. Y. Sano, J. Harada, S. Tashiro, R. Gotoh-Mandeville, T. Maekawa, and S. Ishii: ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling. J Biol Chem 274, 8949-8957 (1999)
doi:10.1074/jbc.274.13.8949
83. K. Kurisaki, A. Kurisaki, U. Valcourt, A.A. Terentiev, K. Pardali, P. Ten Dijke, C.H. Heldin, J. Ericsson, and A. Moustakas: Nuclear factor YY1 inhibits transforming growth factor beta- and bone morphogenetic protein-induced cell differentiation. Mol Cell Biol 23, 4494-4510 (2003)
doi:10.1128/MCB.23.13.4494-4510.2003
84. K. Miyazono, P. ten Dijke, and C.H. Heldin: TGF-beta signaling by Smad proteins. Adv Immunol 75, 115-157 (2000)
doi:10.1016/S0065-2776(00)75003-6
85. S.H. Durand, A. Romeas, M.L. Couble, D. Langlois, J.Y. Li, H. Magloire, F. Bleicher, M.J. Staquet, and J.C. Farges: Expression of the TGF-beta/BMP inhibitor EVI1 in human dental pulp cells. Arch Oral Biol 52, 712-719 (2007)
doi:10.1016/j.archoralbio.2007.01.012
86. K. Luo, S.L. Stroschein, W. Wang, D. Chen, E. Martens, S. Zhou, and Q. Zhou: The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 13, 2196-2206 (1999)
doi:10.1101/gad.13.17.2196
87. F.M. Spagnoli and A.H. Brivanlou: The Gata5 target, TGIF2, defines the pancreatic region by modulating BMP signals within the endoderm. Development 135, 451-461 (2008)
doi:10.1242/dev.008458
88. D. Wotton and J. Massague: Smad transcriptional corepressors in TGF beta family signaling. Curr Top Microbiol Immunol 254, 145-164 (2001)
89. W. Wang, F.V. Mariani, R.M. Harland, and K. Luo: Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc Natl Acad Sci U S A 97, 14394-14399 (2000)
doi:10.1073/pnas.97.26.14394
90. W. Xu, K. Angelis, D. Danielpour, M.M. Haddad, O. Bischof, J. Campisi, E. Stavnezer, and E.E. Medrano: Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc Natl Acad Sci U S A 97, 5924-5929 (2000)
doi:10.1073/pnas.090097797
92. Y. Yoshida, A. von Bubnoff, N. Ikematsu, I.L. Blitz, J.K. Tsuzuku, E.H. Yoshida, H. Umemori, K. Miyazono, T. Yamamoto, and K.W. Cho: Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev 120, 629-637 (2003)
doi:10.1016/S0925-4773(03)00020-0
93. M. Takeda, M. Mizuide, M. Oka, T. Watabe, H. Inoue, H. Suzuki, T. Fujita, T. Imamura, K. Miyazono, and K. Miyazawa: Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski. Mol Biol Cell 15, 963-972 (2004)
doi:10.1091/mbc.E03-07-0478
94. J. Massague and Y.G. Chen: Controlling TGF-beta signaling. Genes Dev 14, 627-644 (2000)
95. X. Liu, Y. Sun, R.A. Weinberg, and H.F. Lodish: Ski/Sno and TGF-beta signaling. Cytokine Growth Factor Rev 12, 1-8 (2001)
doi:10.1016/S1359-6101(00)00031-9
96. K. Arora and R. Warrior: A new Smurf in the village. Dev Cell 1, 441-442 (2001)
doi:10.1016/S1534-5807(01)00067-3
97. H. Zhu, P. Kavsak, S. Abdollah, J.L. Wrana, and G.H. Thomsen: A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687-693 (1999)
doi:10.1038/23293
98. G. Murakami, T. Watabe, K. Takaoka, K. Miyazono, and T. Imamura: Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14, 2809-2817 (2003)
doi:10.1091/mbc.E02-07-0441
99. H. Kaneki, R. Guo, D. Chen, Z. Yao, E.M. Schwarz, Y.E. Zhang, B.F. Boyce, and L. Xing: Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281, 4326-4333 (2006)
doi:10.1074/jbc.M509430200
100. T. Ebisawa, M. Fukuchi, G. Murakami, T. Chiba, K. Tanaka, T. Imamura, and K. Miyazono: Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276, 12477-12480 (2001)
doi:10.1074/jbc.C100008200
101. D. Koinuma, M. Shinozaki, A. Komuro, K. Goto, M. Saitoh, A. Hanyu, M. Ebina, T. Nukiwa, K. Miyazawa, T. Imamura, and K. Miyazono: Arkadia amplifies TGF-beta superfamily signaling through degradation of Smad7. EMBO J 22, 6458-6470 (2003)
doi:10.1093/emboj/cdg632
102. G. Kuratomi, A. Komuro, K. Goto, M. Shinozaki, K. Miyazawa, K. Miyazono, and T. Imamura: NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signaling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J 386, 461-470 (2005)
doi:10.1042/BJ20040738
103. S.J. Wicks, K. Haros, M. Maillard, L. Song, R.E. Cohen, P.T. Dijke, and A. Chantry: The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signaling. Oncogene 24, 8080-8084 (2005)
doi:10.1038/sj.onc.1208944
104. L. Ye, J.M. Lewis-Russell, H.G. Kyanaston, and W.G. Jiang: Bone morphogenetic proteins and their receptor signaling in prostate cancer. Histol Histopathol 22, 1129-1147 (2007)
105. L. Ye, S.M. Bokobza, and W.G. Jiang: Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (review). Int J Mol Med 24, 591-597 (2009)
doi:10.3892/ijmm_00000269
106. H. Bentley, F.C. Hamdy, K.A. Hart, J.M. Seid, J.L. Williams, D. Johnstone, and R.G. Russell: Expression of bone morphogenetic proteins in human prostatic adenocarcinoma and benign prostatic hyperplasia. Br J Cancer 66, 1159-1163 (1992)
107. J. Barnes, C.T. Anthony, N. Wall, and M.S. Steiner: Bone morphogenetic protein-6 expression in normal and malignant prostate. World J Urol 13, 337-343 (1995)
doi:10.1007/BF00191214
108. F.C. Hamdy, P. Autzen, M.C. Robinson, C.H. Horne, D.E. Neal, and C.N. Robson: Immunolocalization and messenger RNA expression of bone morphogenetic protein-6 in human benign and malignant prostatic tissue. Cancer Res 57, 4427-4431 (1997)
109. H. Tamada, R. Kitazawa, K. Gohji, and S. Kitazawa: Epigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancer. J Bone Miner Res 16, 487-496 (2001)
doi:10.1359/jbmr.2001.16.3.487
110. S.E. Harris, M.A. Harris, P. Mahy, J. Wozney, J.Q. Feng, and G.R. Mundy: Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate 24, 204-211 (1994)
doi:10.1002/pros.2990240406
111. R. Thomas, L.D. True, P.H. Lange, and R.L. Vessella: Placental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: relation to tumor development and progression. Int J Cancer 93, 47-52 (2001)
doi:10.1002/ijc.1291
112. L.G. Horvath, S.M. Henshall, J.G. Kench, J.J. Turner, D. Golovsky, P.C. Brenner, G.F. O'Neill, R. Kooner, P.D. Stricker, J.J. Grygiel, and R.L. Sutherland: Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression. Prostate 59, 234-242 (2004)
doi:10.1002/pros.10361
113. H. Masuda, Y. Fukabori, K. Nakano, N. Shimizu, and H. Yamanaka: Expression of bone morphogenetic protein-7 (BMP-7) in human prostate. Prostate 59, 101-106 (2004)
doi:10.1002/pros.20030
114. L. Ye, H. Kynaston, and W.G. Jiang: Bone morphogenetic protein-9 induces apoptosis in prostate cancer cells, the role of prostate apoptosis response-4. Mol Cancer Res 6, 1594-1606 (2008)
doi:10.1158/1541-7786.MCR-08-0171
115. L. Ye, H. Kynaston, and W.G. Jiang: Bone morphogenetic protein-10 suppresses the growth and aggressiveness of prostate cancer cells through a Smad independent pathway. J Urol 181, 2749-2759 (2009)
doi:10.1016/j.juro.2009.01.098
116. I.Y. Kim, D.H. Lee, H.J. Ahn, H. Tokunaga, W. Song, L.M. Devereaux, D. Jin, T.K. Sampath, and R.A. Morton: Expression of bone morphogenetic protein receptors type-IA, -IB and -II correlates with tumor grade in human prostate cancer tissues. Cancer Res 60, 2840-2844 (2000)
117. I.Y. Kim, D.H. Lee, D.K. Lee, H.J. Ahn, M.M. Kim, S.J. Kim, and R.A. Morton: Loss of expression of bone morphogenetic protein receptor type II in human prostate cancer cells. Oncogene 23, 7651-7659 (2004)
doi:10.1038/sj.onc.1207924
118. H. Ide, M. Katoh, H. Sasaki, T. Yoshida, K. Aoki, Y. Nawa, Y. Osada, T. Sugimura, and M. Terada: Cloning of human bone morphogenetic protein type IB receptor (BMPR-IB) and its expression in prostate cancer in comparison with other BMPRs. Oncogene 14, 1377-1382 (1997)
doi:10.1038/sj.onc.1200964
119. S.R. Davies, G. Watkins, A. Douglas-Jones, R.E. Mansel, and W.G. Jiang: Bone morphogenetic proteins 1 to 7 in human breast cancer, expression pattern and clinical/prognostic relevance. J Exp Ther Oncol 7, 327-338 (2008)
120. S. Hanavadi, T.A. Martin, G. Watkins, R.E. Mansel, and W.G. Jiang: The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer. Ann Surg Oncol 14, 2159-2166 (2007)
doi:10.1245/s10434-007-9397-5
121. J. Li, L. Ye, C. Parr, A. Douglas-Jones, H.G. Kyanaston, R.E. Mansel, and W.G. Jiang: The aberrant expression of bone morphogenetic protein 12 (BMP-12) in human breast cancer and its potential prognostic value. Gene Ther Mol Biol 13, 186-193 (2009)
122. J.H. Clement, J. Sanger, and K. Hoffken: Expression of bone morphogenetic protein 6 in normal mammary tissue and breast cancer cell lines and its regulation by epidermal growth factor. Int J Cancer 80, 250-256 (1999)
doi:10.1002/(SICI)1097-0215(19990118)80:2<250::AID-IJC14>3.0.CO;2-D
123. M.M. Reinholz, S.J. Iturria, J.N. Ingle, and P.C. Roche: Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 74, 255-269 (2002)
doi:10.1023/A:1016339120506
124. J.T. Buijs, N.V. Henriquez, P.G. van Overveld, G. van der Horst, I. Que, R. Schwaninger, C. Rentsch, P. Ten Dijke, A.M. Cleton-Jansen, K. Driouch, R. Lidereau, R. Bachelier, S. Vukicevic, P. Clezardin, S.E. Papapoulos, M.G. Cecchini, C.W. Lowik, and G. van der Pluijm: Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res 67, 8742-8751 (2007)
doi:10.1158/0008-5472.CAN-06-2490
125. D. Bobinac, I. Maric, S. Zoricic, J. Spanjol, G. Dordevic, E. Mustac, and Z. Fuckar: Expression of bone morphogenetic proteins in human metastatic prostate and breast cancer. Croat Med J 46, 389-396 (2005)
126. M. Raida, J.H. Clement, K. Ameri, C. Han, R.D. Leek, and A.L. Harris: Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death. Int J Oncol 26, 1465-1470 (2005)
127. E.L. Alarmo, J. Rauta, P. Kauraniemi, R. Karhu, T. Kuukasjarvi, and A. Kallioniemi: Bone morphogenetic protein 7 is widely overexpressed in primary breast cancer. Genes Chromosomes Cancer 45, 411-419 (2006)
doi:10.1002/gcc.20307
128. E.L. Alarmo, T. Kuukasjarvi, R. Karhu, and A. Kallioniemi: A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of BMP4 and BMP7. Breast Cancer Res Treat 103, 239-246 (2007)
doi:10.1007/s10549-006-9362-1
129. M.W. Helms, J. Packeisen, C. August, B. Schittek, W. Boecker, B.H. Brandt, and H. Buerger: First evidence supporting a potential role for the BMP/SMAD pathway in the progression of oestrogen receptor-positive breast cancer. J Pathol 206, 366-376 (2005)
doi:10.1002/path.1785
130. S.M. Bokobza, L. Ye, H.E. Kynaston, R.E. Mansel, and W.G. Jiang: Reduced expression of BMPR-IB correlates with poor prognosis and increased proliferation of breast cancer cells. Cancer Genomics Proteomics 6, 101-108 (2009)
131. Y. Katsuno, A. Hanyu, H. Kanda, Y. Ishikawa, F. Akiyama, T. Iwase, E. Ogata, S. Ehata, K. Miyazono, and T. Imamura: Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322-6333 (2008)
doi:10.1038/onc.2008.232
132. K.D. Brubaker, E. Corey, L.G. Brown, and R.L. Vessella: Bone morphogenetic protein signaling in prostate cancer cell lines. J Cell Biochem 91, 151-160 (2004)
doi:10.1002/jcb.10679
133. N. Ghosh-Choudhury, G. Ghosh-Choudhury, A. Celeste, P.M. Ghosh, M. Moyer, S.L. Abboud, and J. Kreisberg: Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells. Biochim Biophys Acta 1497, 186-196 (2000)
doi:10.1016/S0167-4889(00)00060-4
134. N. Ghosh-Choudhury, K. Woodruff, W. Qi, A. Celeste, S.L. Abboud, and G. Ghosh Choudhury: Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun 272, 705-711 (2000)
doi:10.1006/bbrc.2000.2844
135. F. Pouliot and C. Labrie: Role of Smad1 and Smad4 proteins in the induction of p21WAF1,Cip1 during bone morphogenetic protein-induced growth arrest in human breast cancer cells. J Endocrinol 172, 187-198 (2002)
doi:10.1677/joe.0.1720187
doi:10.1158/0008-5472.CAN-04-2251
137. J. Du, S. Yang, Z. Wang, C. Zhai, W. Yuan, R. Lei, J. Zhang, and T. Zhu: Bone morphogenetic protein 6 inhibit stress-induced breast cancer cells apoptosis via both Smad and p38 pathways. J Cell Biochem 103, 1584-1597 (2008)
doi:10.1002/jcb.21547
138. M. Takahashi, F. Otsuka, T. Miyoshi, H. Otani, J. Goto, M. Yamashita, T. Ogura, H. Makino, and H. Doihara: Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation. J Endocrinol 199, 445-455 (2008)
doi:10.1677/JOE-08-0226
139. R. Montesano, R. Sarkozi, and H. Schramek: Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells. Biochem Biophys Res Commun 374, 164-168 (2008)
doi:10.1016/j.bbrc.2008.07.007
140. E.L. Alarmo, J. Parssinen, J.M. Ketolainen, K. Savinainen, R. Karhu, and A. Kallioniemi: BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett 275, 35-43 (2009)
doi:10.1016/j.canlet.2008.09.028
141. H. Miyazaki, T. Watabe, T. Kitamura, and K. Miyazono: BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells. Oncogene 23, 9326-9335 (2004)
doi:10.1038/sj.onc.1208127
142. F. Pouliot, A. Blais, and C. Labrie: Overexpression of a dominant negative type II bone morphogenetic protein receptor inhibits the growth of human breast cancer cells. Cancer Res 63, 277-281 (2003)
PMid:12543773
143. N. Dumont and C.L. Arteaga: A kinase-inactive type II TGFbeta receptor impairs BMP signaling in human breast cancer cells. Biochem Biophys Res Commun 301, 108-112 (2003)
doi:10.1016/S0006-291X(02)02977-7
144. S.M. Bokobza, L. Ye, H.E. Kynaston, R.E. Mansel, and W.G. Jiang: Reduced expression of BMPR-IB correlates with poor prognosis and increased proliferation of breast cancer cells. Cancer Genomics Proteomics 6, 101-108 (2009)
145. H. Ide, T. Yoshida, N. Matsumoto, K. Aoki, Y. Osada, T. Sugimura, and M. Terada: Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res 57, 5022-5027 (1997)
146. T.B. Ro, R.U. Holt, A.T. Brenne, H. Hjorth-Hansen, A. Waage, O. Hjertner, A. Sundan, and M. Borset: Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Oncogene 23, 3024-3032 (2004)
doi:10.1038/sj.onc.1207386
147. O. Korchynskyi, K.J. Dechering, A.M. Sijbers, W. Olijve, and P. ten Dijke: Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation. J Bone Miner Res 18, 1177-1185 (2003)
doi:10.1359/jbmr.2003.18.7.1177
148. S. Buckley, W. Shi, B. Driscoll, A. Ferrario, K. Anderson, and D. Warburton: BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol 286, L81-86 (2004)
doi:10.1152/ajplung.00160.2003
149. A.R. Hallahan, J.I. Pritchard, R.A. Chandraratna, R.G. Ellenbogen, J.R. Geyer, R.P. Overland, A.D. Strand, S.J. Tapscott, and J.M. Olson: BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 9, 1033-1038 (2003)
doi:10.1038/nm904
150. J. Xu, T.R. Kimball, J.N. Lorenz, D.A. Brown, A.R. Bauskin, R. Klevitsky, T.E. Hewett, S.N. Breit, and J.D. Molkentin: GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 98, 342-350 (2006)
doi:10.1161/01.RES.0000202804.84885.d0
151. O. Hjertner, H. Hjorth-Hansen, M. Borset, C. Seidel, A. Waage, and A. Sundan: Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood 97, 516-522 (2001)
doi:10.1182/blood.V97.2.516
152. S. Yang, C. Zhong, B. Frenkel, A.H. Reddi, and P. Roy-Burman: Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res 65, 5769-5777 (2005)
doi:10.1158/0008-5472.CAN-05-0289
153. S. Yang, M. Lim, L.K. Pham, S.E. Kendall, A.H. Reddi, D.C. Altieri, and P. Roy-Burman: Bone morphogenetic protein 7 protects prostate cancer cells from stress-induced apoptosis via both Smad and c-Jun NH2-terminal kinase pathways. Cancer Res 66, 4285-4290 (2006)
doi:10.1158/0008-5472.CAN-05-4456
154. J.H. Clement, N. Marr, A. Meissner, M. Schwalbe, W. Sebald, K.O. Kliche, K. Hoffken, and S. Wolfl: Bone morphogenetic protein 2 (BMP-2) induces sequential changes of Id gene expression in the breast cancer cell line MCF-7. J Cancer Res Clin Oncol 126, 271-279 (2000)
doi:10.1007/s004320050342
155. S. Steinert, T.C. Kroll, I. Taubert, L. Pusch, P. Hortschansky, K. Hoffken, S. Wolfl, and J.H. Clement: Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2. J Cancer Res Clin Oncol 134, 1237-1245 (2008)
doi:10.1007/s00432-008-0396-0
156. J.P. Thiery and J.P. Sleeman: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7, 131-142 (2006)
doi:10.1038/nrm1835
157. Y. Nakajima, T. Yamagishi, S. Hokari, and H. Nakamura: Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). Anat Rec 258, 119-127 (2000)
doi:10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U
158. L.A. Romano and R.B. Runyan: Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev Biol 223, 91-102 (2000)
doi:10.1006/dbio.2000.9750
159. M. Zeisberg, A.A. Shah, and R. Kalluri: Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem 280, 8094-8100 (2005)
doi:10.1074/jbc.M413102200
160. M. Zeisberg, J. Hanai, H. Sugimoto, T. Mammoto, D. Charytan, F. Strutz, and R. Kalluri: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9, 964-968 (2003)
doi:10.1038/nm888
161. R. Montesano: Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth. Biochem Biophys Res Commun 353, 817-822 (2007)
doi:10.1016/j.bbrc.2006.12.109
162. E. Piek, A. Moustakas, A. Kurisaki, C.H. Heldin, and P. ten Dijke: TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112 (Pt 24), 4557-4568 (1999)
163. S. Yang, J. Du, Z. Wang, W. Yuan, Y. Qiao, M. Zhang, J. Zhang, S. Gao, J. Yin, B. Sun, and T. Zhu: BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells. BMC Cancer 7, 211 (2007)
doi:10.1186/1471-2407-7-211
164. M. Kowanetz, U. Valcourt, R. Bergstrom, C.H. Heldin, and A. Moustakas: Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein. Mol Cell Biol 24, 4241-4254 (2004)
doi:10.1128/MCB.24.10.4241-4254.2004
165. T. Ogata, J.M. Wozney, R. Benezra, and M. Noda: Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells. Proc Natl Acad Sci U S A 90, 9219-9222 (1993)
doi:10.1073/pnas.90.19.9219
166. E.M. Langenfeld, Y. Kong, and J. Langenfeld: Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin. Mol Cancer Res 3, 679-684 (2005)
doi:10.1158/1541-7786.MCR-05-0124
167. E.M. Langenfeld, S.E. Calvano, F. Abou-Nukta, S.F. Lowry, P. Amenta, and J. Langenfeld: The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis 24, 1445-1454 (2003)
doi:10.1093/carcin/bgg100
168. T. Rothhammer, I. Poser, F. Soncin, F. Bataille, M. Moser, and A.K. Bosserhoff: Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res 65, 448-456 (2005)
169. J.H. Clement, M. Raida, J. Sanger, R. Bicknell, J. Liu, A. Naumann, A. Geyer, A. Waldau, P. Hortschansky, A. Schmidt, K. Hoffken, S. Wolft, and A.L. Harris: Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol 27, 401-407 (2005)
170. A. Scherberich, R.P. Tucker, M. Degen, M. Brown-Luedi, A.C. Andres, and R. Chiquet-Ehrismann: Tenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitro. Oncogene 24, 1525-1532 (2005)
doi:10.1038/sj.onc.1208342
171. O. Gautschi, C.G. Tepper, P.R. Purnell, Y. Izumiya, C.P. Evans, T.P. Green, P.Y. Desprez, P.N. Lara, D.R. Gandara, P.C. Mack, and H.J. Kung: Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer. Cancer Res 68, 2250-2258 (2008)
doi:10.1158/0008-5472.CAN-07-6403
172. B.T. Feeley, S.C. Gamradt, W.K. Hsu, N. Liu, L. Krenek, P. Robbins, J. Huard, and J.R. Lieberman: Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res 20, 2189-2199 (2005)
doi:10.1359/JBMR.050802
173. J. Dai, J. Keller, J. Zhang, Y. Lu, Z. Yao, and E.T. Keller: Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res 65, 8274-8285 (2005)
doi:10.1158/0008-5472.CAN-05-1891
174. B.T. Feeley, L. Krenek, N. Liu, W.K. Hsu, S.C. Gamradt, E.M. Schwarz, J. Huard, and J.R. Lieberman: Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38, 154-166 (2006)
175. N. Johansson, U. Saarialho-Kere, K. Airola, R. Herva, L. Nissinen, J. Westermarck, E. Vuorio, J. Heino, and V.M. Kahari: Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development. Dev Dyn 208, 387-397 (1997)
doi:10.1002/(SICI)1097-0177(199703)208:3<387::AID-AJA9>3.0.CO;2-E
176. R. Thomas, W.A. Anderson, V. Raman, and A.H. Reddi: Androgen-dependent gene expression of bone morphogenetic protein 7 in mouse prostate. Prostate 37, 236-245 (1998)
doi:10.1002/(SICI)1097-0045(19981201)37:4<236::AID-PROS5>3.0.CO;2-C
177. M. Zhang, Q. Wang, W. Yuan, S. Yang, X. Wang, J.D. Yan, J. Du, J. Yin, S.Y. Gao, B.C. Sun, and T.H. Zhu: Epigenetic regulation of bone morphogenetic protein-6 gene expression in breast cancer cells. J Steroid Biochem Mol Biol 105, 91-97 (2007)
doi:10.1016/j.jsbmb.2007.01.002
178. M. Schwalbe, J. Sanger, R. Eggers, A. Naumann, A. Schmidt, K. Hoffken, and J.H. Clement: Differential expression and regulation of bone morphogenetic protein 7 in breast cancer. Int J Oncol 23, 89-95 (2003)
179. A. van den Wijngaard, W.R. Mulder, R. Dijkema, C.J. Boersma, S. Mosselman, E.J. van Zoelen, and W. Olijve: Antiestrogens specifically up-regulate bone morphogenetic protein-4 promoter activity in human osteoblastic cells. Mol Endocrinol 14, 623-633 (2000)
doi:10.1210/me.14.5.623
180. T. Yamamoto, F. Saatcioglu, and T. Matsuda: Cross-talk between bone morphogenic proteins and estrogen receptor signaling. Endocrinology 143, 2635-2642 (2002)
doi:10.1210/en.143.7.2635
doi:10.1074/jbc.M212332200
182. S. Kitazawa, R. Kitazawa, C. Obayashi, and T. Yamamoto: Desmoid tumor with ossification in chest wall: possible involvement of BAMBI promoter hypermethylation in metaplastic bone formation. J Bone Miner Res 20, 1472-1477 (2005)
doi:10.1359/jbmr.2005.20.8.1472
183. X.Z. Wen, Y. Akiyama, S.B. Baylin, and Y. Yuasa: Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas. Oncogene 25, 2666-2673 (2006)
doi:10.1038/sj.onc.1209297
184. R.P. Nacamuli, K.D. Fong, K.A. Lenton, H.M. Song, T.D. Fang, A. Salim, and M.T. Longaker: Expression and possible mechanisms of regulation of BMP3 in rat cranial sutures. Plast Reconstr Surg 116, 1353-1362 (2005)
doi:10.1097/01.prs.0000182223.85978.34
185. H.G. van der Poel, C. Hanrahan, H. Zhong, and J.W. Simons: Rapamycin induces Smad activity in prostate cancer cell lines. Urol Res 30, 380-386 (2003)
186. L. Ye, J.M. Lewis-Russell, A.J. Sanders, H. Kynaston, and W.G. Jiang: HGF/SF up-regulates the expression of bone morphogenetic protein 7 in prostate cancer cells. Urol Oncol 26, 190-197 (2008)
doi:10.1016/j.urolonc.2007.03.027
187. L. Ye, J.M. Lewis-Russell, G. Davies, A.J. Sanders, H. Kynaston, and W.G. Jiang: Hepatocyte growth factor up-regulates the expression of the bone morphogenetic protein (BMP) receptors, BMPR-IB and BMPR-II, in human prostate cancer cells. Int J Oncol 30, 521-529 (2007)
188. A.H. Reddi, D. Roodman, C. Freeman, and S. Mohla: Mechanisms of tumor metastasis to the bone: challenges and opportunities. J Bone Miner Res 18, 190-194 (2003)
doi:10.1359/jbmr.2003.18.2.190
189. M.B. Choueiri, S.M. Tu, L.Y. Yu-Lee, and S.H. Lin: The central role of osteoblasts in the metastasis of prostate cancer. Cancer Metastasis Rev 25, 601-609 (2006)
doi:10.1007/s10555-006-9034-y
190. L. Ye, H.G. Kynaston, and W.G. Jiang: Bone metastasis in prostate cancer: molecular and cellular mechanisms (Review). Int J Mol Med 20, 103-111 (2007)
191. Y. Takuwa, T. Masaki, and K. Yamashita: The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae. Biochem Biophys Res Commun 170, 998-1005 (1990)
doi:10.1016/0006-291X(90)90491-5
192. J.B. Nelson, S.P. Hedican, D.J. George, A.H. Reddi, S. Piantadosi, M.A. Eisenberger, and J.W. Simons: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1, 944-949 (1995)
doi:10.1038/nm0995-944
193. S. Granchi, S. Brocchi, L. Bonaccorsi, E. Baldi, M.C. Vinci, G. Forti, M. Serio, and M. Maggi: Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. Prostate 49, 267-277 (2001)
doi:10.1002/pros.10022
194. J.J. Yin, K.S. Mohammad, S.M. Kakonen, S. Harris, J.R. Wu-Wong, J.L. Wessale, R.J. Padley, I.R. Garrett, J.M. Chirgwin, and T.A. Guise: A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 100, 10954-10959 (2003)
doi:10.1073/pnas.1830978100
195. M.A. Carducci, R.J. Padley, J. Breul, N.J. Vogelzang, B.A. Zonnenberg, D.D. Daliani, C.C. Schulman, A.A. Nabulsi, R.A. Humerickhouse, M.A. Weinberg, J.L. Schmitt, and J.B. Nelson: Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 21, 679-689 (2003)
doi:10.1200/JCO.2003.04.176
196. G.A. Clines, K.S. Mohammad, Y. Bao, O.W. Stephens, L.J. Suva, J.D. Shaughnessy, Jr., J.W. Fox, J.M. Chirgwin, and T.A. Guise: Dickkopf Homolog 1 Mediates Endothelin-1-Stimulated New Bone Formation*. Mol Endocrinol (2006)
197. J.B. Nelson, K. Chan-Tack, S.P. Hedican, S.R. Magnuson, T.J. Opgenorth, G.S. Bova, and J.W. Simons: Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res 56, 663-668 (1996)
198. M. Mehrotra, S.M. Krane, K. Walters, and C. Pilbeam: Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells. J Cell Biochem 93, 741-752 (2004)
doi:10.1002/jcb.20138
199. B. Yi, P.J. Williams, M. Niewolna, Y. Wang, and T. Yoneda: Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res 62, 917-923 (2002)
200. C.R. Dunstan, R. Boyce, B.F. Boyce, I.R. Garrett, E. Izbicka, W.H. Burgess, and G.R. Mundy: Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone loss and increases new bone formation in ovariectomized rats. J Bone Miner Res 14, 953-959 (1999)
doi:10.1359/jbmr.1999.14.6.953
201. J.M. Chan, M.J. Stampfer, E. Giovannucci, P.H. Gann, J. Ma, P. Wilkinson, C.H. Hennekens, and M. Pollak: Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563-566 (1998)
doi:10.1126/science.279.5350.563
202. S.F. Shariat, D.J. Lamb, M.W. Kattan, C. Nguyen, J. Kim, J. Beck, T.M. Wheeler, and K.M. Slawin: Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and -3 with prostate cancer invasion, progression, and metastasis. J Clin Oncol 20, 833-841 (2002)
doi:10.1200/JCO.20.3.833
203. J.M. Chan, M.J. Stampfer, J. Ma, P. Gann, J.M. Gaziano, M. Pollak, and E. Giovannucci: Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94, 1099-1106 (2002)
PMid:12122101
204. J. Rubin, X. Fan, J. Rahnert, B. Sen, C.L. Hsieh, T.C. Murphy, M.S. Nanes, L.G. Horton, W.G. Beamer, and C.J. Rosen: IGF-I secretion by prostate carcinoma cells does not alter tumor-bone cell interactions in vitro or in vivo. Prostate 66, 789-800 (2006)
doi:10.1002/pros.20379
205. H.P. Gerber, T.H. Vu, A.M. Ryan, J. Kowalski, Z. Werb, and N. Ferrara: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5, 623-628 (1999)
doi:10.1038/9467
206. J. Street, M. Bao, L. deGuzman, S. Bunting, F.V. Peale, Jr., N. Ferrara, H. Steinmetz, J. Hoeffel, J.L. Cleland, A. Daugherty, N. van Bruggen, H.P. Redmond, R.A. Carano, and E.H. Filvaroff: Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 99, 9656-9661 (2002)
doi:10.1073/pnas.152324099
207. V. Midy and J. Plouet: Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun 199, 380-386 (1994)
doi:10.1006/bbrc.1994.1240
208. J. Dai, Y. Kitagawa, J. Zhang, Z. Yao, A. Mizokami, S. Cheng, J. Nor, L.K. McCauley, R.S. Taichman, and E.T. Keller: Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. Cancer Res 64, 994-999 (2004)
doi:10.1158/0008-5472.CAN-03-1382
209. J. Chen, S. De, J. Brainard, and T.V. Byzova: Metastatic properties of prostate cancer cells are controlled by VEGF. Cell Commun Adhes 11, 1-11 (2004)
doi:10.1080/15419060490471739
210. T. Krupski, M.A. Harding, M.E. Herce, K.M. Gulding, M.H. Stoler, and D. Theodorescu: The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells. Growth Factors 18, 287-302 (2001)
doi:10.3109/08977190109029117
211. G. Chen, N. Shukeir, A. Potti, K. Sircar, A. Aprikian, D. Goltzman, and S.A. Rabbani: Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 101, 1345-1356 (2004)
doi:10.1002/cncr.20518
212. C.L. Hall, S. Kang, O.A. MacDougald, and E.T. Keller: Role of Wnts in prostate cancer bone metastases. J Cell Biochem 97, 661-672 (2006)
doi:10.1002/jcb.20735
213. E. Tian, F. Zhan, R. Walker, E. Rasmussen, Y. Ma, B. Barlogie, and J.D. Shaughnessy, Jr.: The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349, 2483-2494 (2003)
doi:10.1056/NEJMoa030847
214. K.D. Schluter, C. Katzer, and H.M. Piper: A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors. Br J Pharmacol 132, 427-432 (2001)
doi:10.1038/sj.bjp.0703830
215. S.D. Cramer, Z. Chen, and D.M. Peehl: Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 156, 526-531 (1996)
doi:10.1016/S0022-5347(01)65919-6
216. A. Achbarou, S. Kaiser, G. Tremblay, L.G. Ste-Marie, P. Brodt, D. Goltzman, and S.A. Rabbani: Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res 54, 2372-2377 (1994)
217. S.A. Rabbani, J. Desjardins, A.W. Bell, D. Banville, A. Mazar, J. Henkin, and D. Goltzman: An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. Biochem Biophys Res Commun 173, 1058-1064 (1990)
doi:10.1016/S0006-291X(05)80893-9
218. M. Koutsilieris: Osteoblastic metastasis in advanced prostate cancer. Anticancer Res 13, 443-449 (1993)
219. C.S. Killian, D.A. Corral, E. Kawinski, and R.I. Constantine: Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors. Biochem Biophys Res Commun 192, 940-947 (1993)
doi:10.1006/bbrc.1993.1506
220. P. Cohen, H.C. Graves, D.M. Peehl, M. Kamarei, L.C. Giudice, and R.G. Rosenfeld: Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab 75, 1046-1053 (1992)
doi:10.1210/jc.75.4.1046
221. P. Cohen, D.M. Peehl, H.C. Graves, and R.G. Rosenfeld: Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol 142, 407-415 (1994)
doi:10.1677/joe.0.1420407
222. F. Vakar-Lopez, C.J. Cheng, J. Kim, G.G. Shi, P. Troncoso, S.M. Tu, L.Y. Yu-Lee, and S.H. Lin: Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol 203, 688-695 (2004)
doi:10.1002/path.1568
223. A.K. Liang, J. Liu, S.A. Mao, V.S. Siu, Y.C. Lee, and S.H. Lin: Expression of recombinant MDA-BF-1 with a kinase recognition site and a 7-histidine tag for receptor binding and purification. Protein Expr Purif 44, 58-64 (2005)
doi:10.1016/j.pep.2005.03.025
224. G.D. Roodman: Mechanisms of bone metastasis. N Engl J Med 350, 1655-1664 (2004)
doi:10.1056/NEJMra030831
225. G.J. Powell, J. Southby, J.A. Danks, R.G. Stillwell, J.A. Hayman, M.A. Henderson, R.C. Bennett, and T.J. Martin: Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 51, 3059-3061 (1991)
doi:10.1210/en.140.10.4451
227. J. de la Mata, H.L. Uy, T.A. Guise, B. Story, B.F. Boyce, G.R. Mundy, and G.D. Roodman: Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. J Clin Invest 95, 2846-2852 (1995)
doi:10.1172/JCI117990
228. N. Kurihara, D. Bertolini, T. Suda, Y. Akiyama, and G.D. Roodman: IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 144, 4226-4230 (1990)
229. F. Basolo, L. Fiore, G. Fontanini, P.G. Conaldi, S. Calvo, V. Falcone, and A. Toniolo: Expression of and response to interleukin 6 (IL6) in human mammary tumors. Cancer Res 56, 3118-3122 (1996)
230. J.Y. Blay, S. Schemann, and M.C. Favrot: Local production of interleukin 6 by renal adenocarcinoma in vivo. J Natl Cancer Inst 86, 238 (1994)
doi:10.1093/jnci/86.3.238
231. S.S. Tabibzadeh, D. Poubouridis, L.T. May, and P.B. Sehgal: Interleukin-6 immunoreactivity in human tumors. Am J Pathol 135, 427-433 (1989)
232. W. Thabard, M. Collette, M.P. Mellerin, D. Puthier, S. Barille, R. Bataille, and M. Amiot: IL-6 upregulates its own receptor on some human myeloma cell lines. Cytokine 14, 352-356 (2001)
doi:10.1006/cyto.2001.0911
233. K. Ono, T. Akatsu, T. Murakami, R. Kitamura, M. Yamamoto, N. Shinomiya, M. Rokutanda, T. Sasaki, N. Amizuka, H. Ozawa, N. Nagata, and N. Kugai: Involvement of cyclo-oxygenase-2 in osteoclast formation and bone destruction in bone metastasis of mammary carcinoma cell lines. J Bone Miner Res 17, 774-781 (2002)
doi:10.1359/jbmr.2002.17.5.774
234. L. Pederson, B. Winding, N.T. Foged, T.C. Spelsberg, and M.J. Oursler: Identification of breast cancer cell line-derived paracrine factors that stimulate osteoclast activity. Cancer Res 59, 5849-5855 (1999)
235. A.T. Mancino, V.S. Klimberg, M. Yamamoto, S.C. Manolagas, and E. Abe: Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res 100, 18-24 (2001)
doi:10.1006/jsre.2001.6204
236. E. Sapi: The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update. Exp Biol Med (Maywood) 229, 1-11 (2004)
237. O.V. Batson: The function of the vertebral veins and their role in the spread of metastases. 1940. Clin Orthop Relat Res 4-9 (1995)
238. A.C. Khodavirdi, Z. Song, S. Yang, C. Zhong, S. Wang, H. Wu, C. Pritchard, P.S. Nelson, and P. Roy-Burman: Increased expression of osteopontin contributes to the progression of prostate cancer. Cancer Res 66, 883-888 (2006)
doi:10.1158/0008-5472.CAN-05-2816
239. K. Fizazi, J. Yang, S. Peleg, C.R. Sikes, E.L. Kreimann, D. Daliani, M. Olive, K.A. Raymond, T.J. Janus, C.J. Logothetis, G. Karsenty, and N.M. Navone: Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts. Clin Cancer Res 9, 2587-2597 (2003)
240. K. Jacob, M. Webber, D. Benayahu, and H.K. Kleinman: Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res 59, 4453-4457 (1999)
241. J.H. Zhang, J. Tang, J. Wang, W. Ma, W. Zheng, T. Yoneda, and J. Chen: Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. Int J Oncol 23, 1043-1048 (2003)
242. D.T. Denhardt, C.M. Giachelli, and S.R. Rittling: Role of osteopontin in cellular signaling and toxicant injury. Annu Rev Pharmacol Toxicol 41, 723-749 (2001)
doi:10.1146/annurev.pharmtox.41.1.723
243. T.J. Rosol: Pathogenesis of bone metastases: role of tumor-related proteins. J Bone Miner Res 15, 844-850 (2000)
doi:10.1359/jbmr.2000.15.5.844
244. A.M. Moursi, C.H. Damsky, J. Lull, D. Zimmerman, S.B. Doty, S. Aota, and R.K. Globus: Fibronectin regulates calvarial osteoblast differentiation. J Cell Sci 109 (Pt 6), 1369-1380 (1996)
245. A.M. Moursi, R.K. Globus, and C.H. Damsky: Interactions between integrin receptors and fibronectin are required for calvarial osteoblast differentiation in vitro. J Cell Sci 110 (Pt 18), 2187-2196 (1997)
246. R.K. Globus, S.B. Doty, J.C. Lull, E. Holmuhamedov, M.J. Humphries, and C.H. Damsky: Fibronectin is a survival factor for differentiated osteoblasts. J Cell Sci 111 (Pt 10), 1385-1393 (1998)
247. J.D. Termine, H.K. Kleinman, S.W. Whitson, K.M. Conn, M.L. McGarvey, and G.R. Martin: Osteonectin, a bone-specific protein linking mineral to collagen. Cell 26, 99-105 (1981)
248. A.M. Delany, M. Amling, M. Priemel, C. Howe, R. Baron, and E. Canalis: Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest 105, 915-923 (2000)
doi:10.1172/JCI7039
249. P. Bornstein, L.C. Armstrong, K.D. Hankenson, T.R. Kyriakides, and Z. Yang: Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biol 19, 557-568 (2000)
doi:10.1016/S0945-053X(00)00104-9
250. K.D. Hankenson and P. Bornstein: The secreted protein thrombospondin 2 is an autocrine inhibitor of marrow stromal cell proliferation. J Bone Miner Res 17, 415-425 (2002)
doi:10.1359/jbmr.2002.17.3.415
251. K.D. Hankenson, I.E. James, S. Apone, G.B. Stroup, S.M. Blake, X. Liang, M.W. Lark, and P. Bornstein: Increased osteoblastogenesis and decreased bone resorption protect against ovariectomy-induced bone loss in thrombospondin-2-null mice. Matrix Biol 24, 362-370 (2005)
doi:10.1016/j.matbio.2005.05.008
252. N. Thapa, K.B. Kang, and I.S. Kim: Beta ig-h3 mediates osteoblast adhesion and inhibits differentiation. Bone 36, 232-242 (2005)
253. J. Skonier, K. Bennett, V. Rothwell, S. Kosowski, G. Plowman, P. Wallace, S. Edelhoff, C. Disteche, M. Neubauer, H. Marquardt, and et al.: beta ig-h3: a transforming growth factor-beta-responsive gene encoding a secreted protein that inhibits cell attachment in vitro and suppresses the growth of CHO cells in nude mice. DNA Cell Biol 13, 571-584 (1994)
doi:10.1089/dna.1994.13.571
254. P. Ducy, C. Desbois, B. Boyce, G. Pinero, B. Story, C. Dunstan, E. Smith, J. Bonadio, S. Goldstein, C. Gundberg, A. Bradley, and G. Karsenty: Increased bone formation in osteocalcin-deficient mice. Nature 382, 448-452 (1996)
doi:10.1038/382448a0
255. G. Luo, P. Ducy, M.D. McKee, G.J. Pinero, E. Loyer, R.R. Behringer, and G. Karsenty: Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386, 78-81 (1997)
doi:10.1038/386078a0
256. G.K. Hunter and H.A. Goldberg: Nucleation of hydroxyapatite by bone sialoprotein. Proc Natl Acad Sci U S A 90, 8562-8565 (1993)
doi:10.1073/pnas.90.18.8562
257. B. Ganss, R.H. Kim, and J. Sodek: Bone sialoprotein. Crit Rev Oral Biol Med 10, 79-98 (1999)
doi:10.1177/10454411990100010401
258. K. Hultenby, F.P. Reinholt, and D. Heinegard: Distribution of integrin subunits on rat metaphyseal osteoclasts and osteoblasts. Eur J Cell Biol 62, 86-93 (1993)
259. F.P. Reinholt, K. Hultenby, A. Oldberg, and D. Heinegard: Osteopontin--a possible anchor of osteoclasts to bone. Proc Natl Acad Sci U S A 87, 4473-4475 (1990)
doi:10.1073/pnas.87.12.4473
260. M. Ishijima, K. Tsuji, S.R. Rittling, T. Yamashita, H. Kurosawa, D.T. Denhardt, A. Nifuji, and M. Noda: Resistance to unloading-induced three-dimensional bone loss in osteopontin-deficient mice. J Bone Miner Res 17, 661-667 (2002)
doi:10.1359/jbmr.2002.17.4.661
261. H. Ihara, D.T. Denhardt, K. Furuya, T. Yamashita, Y. Muguruma, K. Tsuji, K.A. Hruska, K. Higashio, S. Enomoto, A. Nifuji, S.R. Rittling, and M. Noda: Parathyroid hormone-induced bone resorption does not occur in the absence of osteopontin. J Biol Chem 276, 13065-13071 (2001)
doi:10.1074/jbc.M010938200
262. M.F. Young: Bone matrix proteins: their function, regulation, and relationship to osteoporosis. Osteoporos Int 14 Suppl 3, S35-42 (2003)
263. S. Wadhwa, M.C. Embree, Y. Bi, and M.F. Young: Regulation, regulatory activities, and function of biglycan. Crit Rev Eukaryot Gene Expr 14, 301-315 (2004)
doi:10.1615/CritRevEukaryotGeneExpr.v14.i4.50
264. Y. Mochida, D. Parisuthiman, and M. Yamauchi: Biglycan is a positive modulator of BMP-2 induced osteoblast differentiation. Adv Exp Med Biol 585, 101-113 (2006)
doi:10.1007/978-0-387-34133-0_7
265. X.D. Chen, L.W. Fisher, P.G. Robey, and M.F. Young: The small leucine-rich proteoglycan biglycan modulates BMP-4-induced osteoblast differentiation. Faseb J 18, 948-958 (2004)
doi:10.1096/fj.03-0899com
266. P. Garnero, N. Buchs, J. Zekri, R. Rizzoli, R.E. Coleman, and P.D. Delmas: Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 82, 858-864 (2000)
doi:10.1054/bjoc.1999.1012
267. A. Lipton, E. Small, F. Saad, D. Gleason, D. Gordon, M. Smith, L. Rosen, M.O. Kowalski, D. Reitsma, and J. Seaman: The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 20 Suppl 2, 45-54 (2002)
doi:10.1081/CNV-120014886
268. Y. Kakehi, T. Segawa, X.X. Wu, P. Kulkarni, R. Dhir, and R.H. Getzenberg: Down-regulation of macrophage inhibitory cytokine-1/prostate derived factor in benign prostatic hyperplasia. Prostate 59, 351-356 (2004)
doi:10.1002/pros.10365
269. H. Masuda, Y. Fukabori, K. Nakano, Y. Takezawa, C.S. T, and H. Yamanaka: Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer. Prostate 54, 268-274 (2003)
doi:10.1002/pros.10193
270. T.G. Hullinger, R.S. Taichman, D.A. Linseman, and M.J. Somerman: Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells. J Cell Biochem 78, 607-616 (2000)
doi:10.1002/1097-4644(20000915)78:4<607::AID-JCB10>3.0.CO;2-F
doi:10.1093/emboj/21.7.1743
272. C. Regazzoni, K.H. Winterhalter, and L. Rohrer: Type I collagen induces expression of bone morphogenetic protein receptor type II. Biochem Biophys Res Commun 283, 316-322 (2001)
doi:10.1006/bbrc.2001.4813
273. T. Nakagawa, J.H. Li, G. Garcia, W. Mu, E. Piek, E.P. Bottinger, Y. Chen, H.J. Zhu, D.H. Kang, G.F. Schreiner, H.Y. Lan, and R.J. Johnson: TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways. Kidney Int 66, 605-613 (2004)
doi:10.1111/j.1523-1755.2004.00780.x
274. S.U. Han, H.T. Kim, D.H. Seong, Y.S. Kim, Y.S. Park, Y.J. Bang, H.K. Yang, and S.J. Kim: Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene 23, 1333-1341 (2004)
doi:10.1038/sj.onc.1207259
275. I. Schwarte-Waldhoff, O.V. Volpert, N.P. Bouck, B. Sipos, S.A. Hahn, S. Klein-Scory, J. Luttges, G. Kloppel, U. Graeven, C. Eilert-Micus, A. Hintelmann, and W. Schmiegel: Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A 97, 9624-9629 (2000)
doi:10.1073/pnas.97.17.9624
276. H. Yamashita, A. Shimizu, M. Kato, H. Nishitoh, H. Ichijo, A. Hanyu, I. Morita, M. Kimura, F. Makishima, and K. Miyazono: Growth/differentiation factor-5 induces angiogenesis in vivo. Exp Cell Res 235, 218-226 (1997)
doi:10.1006/excr.1997.3664
277. S. Mori, H. Yoshikawa, J. Hashimoto, T. Ueda, H. Funai, M. Kato, and K. Takaoka: Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2. Bone 22, 99-105 (1998)
278. L.C. Yeh and J.C. Lee: Osteogenic protein-1 increases gene expression of vascular endothelial growth factor in primary cultures of fetal rat calvaria cells. Mol Cell Endocrinol 153, 113-124 (1999)
doi:10.1016/S0303-7207(99)00076-3
279. J. Glienke, A.O. Schmitt, C. Pilarsky, B. Hinzmann, B. Weiss, A. Rosenthal, and K.H. Thierauch: Differential gene expression by endothelial cells in distinct angiogenic states. Eur J Biochem 267, 2820-2830 (2000)
doi:10.1046/j.1432-1327.2000.01325.x
280. M.M. Deckers, R.L. van Bezooijen, G. van der Horst, J. Hoogendam, C. van Der Bent, S.E. Papapoulos, and C.W. Lowik: Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 143, 1545-1553 (2002)
doi:10.1210/en.143.4.1545
281. L.N. Ramoshebi and U. Ripamonti: Osteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor-beta1. Anat Rec 259, 97-107 (2000)
doi:10.1002/(SICI)1097-0185(20000501)259:1<97::AID-AR11>3.0.CO;2-O
282. M. Scharpfenecker, M. van Dinther, Z. Liu, R.L. van Bezooijen, Q. Zhao, L. Pukac, C.W. Lowik, and P. ten Dijke: BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 120, 964-972 (2007)
doi:10.1242/jcs.002949
283. J.E. Moreau, K. Anderson, J.R. Mauney, T. Nguyen, D.L. Kaplan, and M. Rosenblatt: Tissue-engineered bone serves as a target for metastasis of human breast cancer in a mouse model. Cancer Res 67, 10304-10308 (2007)
doi:10.1158/0008-5472.CAN-07-2483
284. P. Bunyaratavej, T.G. Hullinger, and M.J. Somerman: Bone morphogenetic proteins secreted by breast cancer cells upregulate bone sialoprotein expression in preosteoblast cells. Exp Cell Res 260, 324-333 (2000)
doi:10.1006/excr.2000.5019
285. R. Schwaninger, C.A. Rentsch, A. Wetterwald, G. van der Horst, R.L. van Bezooijen, G. van der Pluijm, C.W. Lowik, K. Ackermann, W. Pyerin, F.C. Hamdy, G.N. Thalmann, and M.G. Cecchini: Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am J Pathol 170, 160-175 (2007)
doi:10.2353/ajpath.2007.051276
286. H. Namkoong, S.M. Shin, H.K. Kim, S.A. Ha, G.W. Cho, S.Y. Hur, T.E. Kim, and J.W. Kim: The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer 6, 74 (2006)
doi:10.1186/1471-2407-6-74
287. Y. Katsuno, A. Hanyu, H. Kanda, Y. Ishikawa, F. Akiyama, T. Iwase, E. Ogata, S. Ehata, K. Miyazono, and T. Imamura: Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27(49):6322-33. (2008)
288. L. Ye, J.M. Lewis-Russell, H. Kynaston, and W.G. Jiang: Endogenous BMP-7 controls the motility of prostate cancer cells through regulation of BMP Antagonists. J Urol in press, (2007)
doi:10.1016/j.juro.2007.05.003
289. B.B. Koenig, J.S. Cook, D.H. Wolsing, J. Ting, J.P. Tiesman, P.E. Correa, C.A. Olson, A.L. Pecquet, F. Ventura, R.A. Grant, and et al.: Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol 14, 5961-5974 (1994)
290. N. Yamaji, A.J. Celeste, R.S. Thies, J.J. Song, S.M. Bernier, D. Goltzman, K.M. Lyons, J. Nove, V. Rosen, and J.M. Wozney: A mammalian serine/threonine kinase receptor specifically binds BMP-2 and BMP-4. Biochem Biophys Res Commun 205, 1944-1951 (1994)
doi:10.1006/bbrc.1994.2898
291. M. Namiki, S. Akiyama, T. Katagiri, A. Suzuki, N. Ueno, N. Yamaji, V. Rosen, J.M. Wozney, and T. Suda: A kinase domain-truncated type I receptor blocks bone morphogenetic protein-2-induced signal transduction in C2C12 myoblasts. J Biol Chem 272, 22046-22052 (1997)
doi:10.1074/jbc.272.35.22046
292. F. Liu, F. Ventura, J. Doody, and J. Massague: Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15, 3479-3486 (1995)
293. A. Daluiski, T. Engstrand, M.E. Bahamonde, L.W. Gamer, E. Agius, S.L. Stevenson, K. Cox, V. Rosen, and K.M. Lyons: Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27, 84-88 (2001)
doi:10.1038/83810
294. P. ten Dijke, H. Yamashita, T.K. Sampath, A.H. Reddi, M. Estevez, D.L. Riddle, H. Ichijo, C.H. Heldin, and K. Miyazono: Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269, 16985-16988 (1994)
295. T. Nohno, T. Ishikawa, T. Saito, K. Hosokawa, S. Noji, D.H. Wolsing, and J.S. Rosenbaum: Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem 270, 22522-22526 (1995)
doi:10.1074/jbc.270.38.22522
296. B.L. Rosenzweig, T. Imamura, T. Okadome, G.N. Cox, H. Yamashita, P. ten Dijke, C.H. Heldin, and K. Miyazono: Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci U S A 92, 7632-7636 (1995)
doi:10.1073/pnas.92.17.7632
297. H. Aoki, M. Fujii, T. Imamura, K. Yagi, K. Takehara, M. Kato, and K. Miyazono: Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. J Cell Sci 114, 1483-1489 (2001)
298. V. Zuzarte-Luis, J.A. Montero, J. Rodriguez-Leon, R. Merino, J.C. Rodriguez-Rey, and J.M. Hurle: A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. Dev Biol 272, 39-52 (2004)
doi:10.1016/j.ydbio.2004.04.015
299. H.N. Beck, K. Drahushuk, D.B. Jacoby, D. Higgins, and P.J. Lein: Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neurosci 2, 12 (2001)
doi:10.1186/1471-2202-2-12
300. N. Ahmed, J. Sammons, R.J. Carson, M.A. Khokher, and H.T. Hassan: Effect of bone morphogenetic protein-6 on haemopoietic stem cells and cytokine production in normal human bone marrow stroma. Cell Biol Int 25, 429-435 (2001)
doi:10.1006/cbir.2000.0662
302. S. Mazerbourg, K. Sangkuhl, C.W. Luo, S. Sudo, C. Klein, and A.J. Hsueh: Identification of receptors and signaling pathways for orphan bone morphogenetic protein/growth differentiation factor ligands based on genomic analyses. J Biol Chem 280, 32122-32132 (2005)
doi:10.1074/jbc.M504629200
303. R.K. Moore, F. Otsuka, and S. Shimasaki: Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J Biol Chem 278, 304-310 (2003)
doi:10.1074/jbc.M207362200
304. S.K. Cheng, F. Olale, J.T. Bennett, A.H. Brivanlou, and A.F. Schier: EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1. Genes Dev 17, 31-36 (2003)
doi:10.1101/gad.1041203
305. I. Lopez-Coviella, T.M. Mellott, V.P. Kovacheva, B. Berse, B.E. Slack, V. Zemelko, A. Schnitzler, and J.K. Blusztajn: Developmental pattern of expression of BMP receptors and Smads and activation of Smad1 and Smad5 by BMP9 in mouse basal forebrain. Brain Res 1088, 49-56 (2006)
doi:10.1016/j.brainres.2006.02.073
306. H. Nishitoh, H. Ichijo, M. Kimura, T. Matsumoto, F. Makishima, A. Yamaguchi, H. Yamashita, S. Enomoto, and K. Miyazono: Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J Biol Chem 271, 21345-21352 (1996)
doi:10.1074/jbc.271.35.21345
307. X. Chen, A. Zankl, F. Niroomand, Z. Liu, H.A. Katus, L. Jahn, and C. Tiefenbacher: Upregulation of ID protein by growth and differentiation factor 5 (GDF5) through a smad-dependent and MAPK-independent pathway in HUVSMC. J Mol Cell Cardiol 41, 26-33 (2006)
doi:10.1016/j.yjmcc.2006.03.421
308. T. Nakahara, K. Tominaga, T. Koseki, M. Yamamoto, K. Yamato, J. Fukuda, and T. Nishihara: Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad. Cell Signal 15, 181-187 (2003)
doi:10.1016/S0898-6568(02)00088-8
309. A. Rebbapragada, H. Benchabane, J.L. Wrana, A.J. Celeste, and L. Attisano: Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol 23, 7230-7242 (2003)
doi:10.1128/MCB.23.20.7230-7242.2003
310. A.C. McPherron, A.M. Lawler, and S.J. Lee: Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet 22, 260-264 (1999)
doi:10.1038/10320
311. S.P. Oh, C.Y. Yeo, Y. Lee, H. Schrewe, M. Whitman, and E. Li: Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev 16, 2749-2754 (2002)
doi:10.1101/gad.1021802
312. O. Andersson, E. Reissmann, and C.F. Ibanez: Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. EMBO Rep 7, 831-837 (2006)
313. R.L. Strausberg, E.A. Feingold, L.H. Grouse, J.G. Derge, R.D. Klausner, F.S. Collins, L. Wagner, C.M. Shenmen, G.D. Schuler, S.F. Altschul, B. Zeeberg, K.H. Buetow, C.F. Schaefer, N.K. Bhat, R.F. Hopkins, H. Jordan, T. Moore, S.I. Max, J. Wang, F. Hsieh, L. Diatchenko, K. Marusina, A.A. Farmer, G.M. Rubin, L. Hong, M. Stapleton, M.B. Soares, M.F. Bonaldo, T.L. Casavant, T.E. Scheetz, M.J. Brownstein, T.B. Usdin, S. Toshiyuki, P. Carninci, C. Prange, S.S. Raha, N.A. Loquellano, G.J. Peters, R.D. Abramson, S.J. Mullahy, S.A. Bosak, P.J. McEwan, K.J. McKernan, J.A. Malek, P.H. Gunaratne, S. Richards, K.C. Worley, S. Hale, A.M. Garcia, L.J. Gay, S.W. Hulyk, D.K. Villalon, D.M. Muzny, E.J. Sodergren, X. Lu, R.A. Gibbs, J. Fahey, E. Helton, M. Ketteman, A. Madan, S. Rodrigues, A. Sanchez, M. Whiting, A.C. Young, Y. Shevchenko, G.G. Bouffard, R.W. Blakesley, J.W. Touchman, E.D. Green, M.C. Dickson, A.C. Rodriguez, J. Grimwood, J. Schmutz, R.M. Myers, Y.S. Butterfield, M.I. Krzywinski, U. Skalska, D.E. Smailus, A. Schnerch, J.E. Schein, S.J. Jones, and M.A. Marra: Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 99, 16899-16903 (2002)
doi:10.1073/pnas.242603899
314. E. Ozkaynak, P.N. Schnegelsberg, D.F. Jin, G.M. Clifford, F.D. Warren, E.A. Drier, and H. Oppermann: Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem 267, 25220-25227 (1992)
315. H. Neuhaus, V. Rosen, and R.S. Thies: Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech Dev 80, 181-184 (1999)
doi:10.1016/S0925-4773(98)00221-4
316. J.L. Dube, P. Wang, J. Elvin, K.M. Lyons, A.J. Celeste, and M.M. Matzuk: The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol Endocrinol 12, 1809-1817 (1998)
doi:10.1210/me.12.12.1809
317. C.T. Rankin, T. Bunton, A.M. Lawler, and S.J. Lee: Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat Genet 24, 262-265 (2000)
doi:10.1038/73472
318. S.J. Lee: Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proc Natl Acad Sci U S A 88, 4250-4254 (1991)
doi:10.1073/pnas.88.10.4250
319. A.J. Celeste, J.J. Song, K. Cox, V. Rosen, and J.M. Wozney: Bone morphogenetic protein-9, a new member of the TGF-beta superfamily. J Bone Min Res Suppl 1, S136 (1994)
321. M. Ye, K.M. Berry-Wynne, M. Asai-Coakwell, P. Sundaresan, T. Footz, C.R. French, M. Abitbol, V.C. Fleisch, N. Corbett, W.T. Allison, G. Drummond, M.A. Walter, T.M. Underhill, A.J. Waskiewicz, and O.J. Lehmann: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum Mol Genet 19, 287-298 (2009)
doi:10.1093/hmg/ddp496
322. O. Andersson, M. Korach-Andre, E. Reissmann, C.F. Ibanez, and P. Bertolino: Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc Natl Acad Sci U S A 105, 7252-7256 (2008)
doi:10.1073/pnas.0800272105
323. G. Hotten, H. Neidhardt, B. Jacobowsky, and J. Pohl: Cloning and expression of recombinant human growth/differentiation factor 5. Biochem Biophys Res Commun 204, 646-652 (1994)
doi:10.1006/bbrc.1994.2508
324. A.J. Davidson, J.H. Postlethwait, Y.L. Yan, D.R. Beier, C. van Doren, D. Foernzler, A.J. Celeste, K.E. Crosier, and P.S. Crosier: Isolation of zebrafish gdf7 and comparative genetic mapping of genes belonging to the growth/differentiation factor 5, 6, 7 subgroup of the TGF-beta superfamily. Genome Res 9, 121-129 (1999)
325. K.J. Lee, M. Mendelsohn, and T.M. Jessell: Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev 12, 3394-3407 (1998)
doi:10.1101/gad.12.21.3394
326. A.C. McPherron, A.M. Lawler, and S.J. Lee: Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83-90 (1997)
doi:10.1038/387083a0
327. N.S. Cunningham, N.A. Jenkins, D.J. Gilbert, N.G. Copeland, A.H. Reddi, and S.J. Lee: Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3. Growth Factors 12, 99-109 (1995)
doi:10.3109/08977199509028956
328. L.W. Gamer, N.M. Wolfman, A.J. Celeste, G. Hattersley, R. Hewick, and V. Rosen: A novel BMP expressed in developing mouse limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos. Dev Biol 208, 222-232 (1999)
doi:10.1006/dbio.1998.9191
329. M. Yokoyama-Kobayashi, M. Saeki, S. Sekine, and S. Kato: Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J Biochem (Tokyo) 122, 622-626 (1997)
330. P. Vanhara, E. Lincova, A. Kozubik, P. Jurdic, K. Soucek, and J. Smarda: Growth/differentiation factor-15 inhibits differentiation into osteoclasts--a novel factor involved in control of osteoclast differentiation. Differentiation 78, 213-222 (2009)
doi:10.1016/j.diff.2009.07.008
331. T. Tanno, N.V. Bhanu, P.A. Oneal, S.H. Goh, P. Staker, Y.T. Lee, J.W. Moroney, C.H. Reed, N.L. Luban, R.H. Wang, T.E. Eling, R. Childs, T. Ganz, S.F. Leitman, S. Fucharoen, and J.L. Miller: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13, 1096-1101 (2007)
doi:10.1038/nm1629