[Frontiers in Bioscience E4, 74-100, January 1, 2012]
Osteoarthritis: genetic factors, animal models, mechanisms, and therapies
Qin Bian123, Yong-Jun Wang12 Shu-fen Liu12, Yi-Ping Li4 Department of Orthopedics and Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No.725 South Wan-ping Road, Shanghai, China, 200032, 2Institute of Spine, Shanghai University of Traditional Chinese Medicine, No.725 South Wan-ping Road, Shanghai, China, 200032, 3Institute of integrated Traditional Chinese Medicine and Western Medicine, Huashan Hospital, Fudan University, No.12 Middle Wu lu mu qi Road, Shanghai, China, 200040, 4Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Blvd,Birmingham AL 35294-2182
TABLE OF CONTENTS
1. ABSTRACT
Osteoarthritis (OA) is the most common form of joint disease. OA frequently affects knees, hips, hands, and the spine. It is characterized by the progressive destruction of articular cartilage and subchondral bone accompanied by low-grade inflammation that together result in pain and deformity. Recent studies have shed light on the nature of OA genetic susceptibility and confirmed a number of candidate genes involved in the destruction of the synovium, articular cartilage, and subchondral bone in OA pathogenesis. During the progression of OA, there are several cellular changes in joints, including an increase in the number of activated osteoclasts and macrophages and an infiltration of the synovium by activated T-cells and B-cells. Pro-inflammatory mediators (e.g. interleukin IL-1, IL-1beta, IL-6, IL-17, and IL-18, and Tumor necrosis actor-alpha), proteinases (e.g. matrix metalloproteinase 9 and cathepsin K), and regulators of cartilage and bone formation (e.g. BMPs) have been shown to have important roles in OA progression at the molecular level. Studies have suggested that OA shares several common characteristics with rheumatoid arthritis (RA). To systematically understand OA, this review summarizes OA disease genes, mouse models of human disease experimental mouse models, mechanisms of OA pathogenesis, and current OA therapies.
2. INTRODUCTION
Epidemiologic data shows that OA affects people in many countries, including 27 million adults in the United States (approximately 10% of the population)(1), and 3 million individuals in Australia (15% of the population)(2). There are multiple risk factors for OA, such as old age, genetic predisposition, sex, trauma, repetitive stress, obesity, inflammation, lifestyle issues, and comorbidities(3). Muscle weakness and afferent sensory dysfunction are considered predictors of OA onset and progression(4). Recently, Hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) was reported to be the most potent transactivator of COL10A1, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with OA. Others such as COL2A1, COL11A1, and AGC1 are related to OA in both humans and genetically-modified animal models. However, there is still long way to go to confirm these mutant genes in OA pathogenesis. Spontaneous models have been used less in recent years because they have been investigated for long periods of time. Currently, the common techniques for model creation are anterior cruciate ligament transaction (ACLT) and enzymatic alteration such as intra-articular injection with papain, trypsin, or collagenase. Genetically modified models such as Cre-Gdf5/Bmpr1afloxP mice, Gt(ROSA)26Sortm1(Smo/YFP)Am-transgenic mice have also been utilized for the study of OA mechanisms. Chondrocytes, osteoclasts, synovial lining cells, and many cytokines and growth factors participate in OA development. MMPs, IL, TNF, Cathepsin K, IGF, TGF, FGF, VEGF, RANKL, etc. BMP-2, 4, 7 and their downstream genes play different roles in OA occurrence and development, especially in disparate components of joints. Although Non-steroidal anti-inflammatory drugs (NSAIDs), glucosamine and chondroitin, are still widely used in clinics, the use of traditional Chinese medicine and acupuncture are becoming popular in OA patients. This review is focused on the genetic background, model systems, cellular and molecular mechanisms, and therapeutic strategies for OA.
3. GENETIC FACTORS
Several studies have demonstrated that some individuals are genetically susceptible to OA. The genes that facilitate this vulnerability are involved in chondroplasia (cartilage development). Below, we demonstrate that the OA mutant genes developed in animal models are similar to those found in humans.
3.1. Cartilage ECM structural genes In order to establish the genetic basis for OA, the initial studies focused on cartilage extracellular matrix (ECM) structural genes, such as COL2A1(12q13.11) that encodes alpha-1 polypeptide chain of type II collagen. Five studies identified five patients and families with the same cysteine for arginine substitution at position alpha-1-519 of the pro-alpha-1(II) chain who showed joint degeneration similar to early-onset OA. Moreover, some have evidence of mild chondrodysplasia; however, other individuals in these studies did not display any symptoms (5,6). Recently, Hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) has been reported to be the most potent transactivator of COL10A1, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee OA in a Japanese population (7).
Mutations in different cartilage collagen genes are also associated with OA. For example, mutations in COL11A1(1p21.1) and COL11A2(6p21.32), encode type XI collagen, cause symptoms such as mild spondyloepiphyseal dysplasia and Stickler Syndrome, a disease characterized by sensorineural hearing loss, caused by a splice donor site mutation resulting in "in-frame" exon skipping(8). A mutation in AGC1(15q26.1) that encodes aggrecan protein is associated with severe, premature OA along with spondyloepiphyseal dysplasia(9). The D14 polymorphism with 14 D residues of ASPN, an extracellular matrix protein, belongs to the SLRP family, and was identified as the risk allele of OA and lumbar disc degeneration. The function of this gene is to inhibit in vitro chondrogenesis and expression of Col2a1 and Agc1 through inhibition of TGF-beta signaling(10,13).
COMP (19p13.11) encodes cartilage oligomeric matrix protein, non-collagenous components, and expresses the phenotype of multiple epiphyseal dysplasia with OA symptoms(14). Matrilin-3, another non-collagenous cartilage extracellular matrix protein, encoded by MATN3(2p24.1), is found to cosegregate with OA of the hands. The missense mutation frequency is slightly greater than 2% in patients in the Icelandic population(15). FRZB (2q32.1), which encodes both the chondrogenic regulator secreted frizzled-related protein 3, and CILP (15q22.31) that codes for a cartilage intermediate-layer protein, has also been reported to be associated with OA in females (16,17).
3.2. Bone mass related genes
OA pathology involves subchondral sclerosis and increased bone density; therefore, attention has also been devoted to genes that encode for proteins influencing bone density. For example, VDR (12p13.11) encodes the vitamin D receptor. CALM1,2 encodes calmodulins, KL encodes an enzyme with a key role in calcium and phosphate homeostasis, CALCA encodes calcitonin. In turn, ESR1 (6q25.1) encodes the oestrogen receptor alpha, BMP2 (20p12.3), BMP5 (6p12.1), that then encodes bone morphogenetic protein and OPG (8q24.12). These latter proteins encode osteoprotegerin. Leptin is a peptide hormone playing a role in bone metabolism. Haplotypes in LEP, a gene encoding leptin is related to OA in Chinese patients. This cascade demonstrates the relatively pronounced association with OA (17-29). However, the effect of these gene mutations on disease occurrence might be moderate for the complex pathogenesis in OA.
3.3. Inflammation related genes
Inflammatory cytokines, which are synthesized not only in synovial cells but also in articular cartilage chondrocytes, play an important role in OA. Polymorphism within the IL-1 cluster gene (2q13) and variation in IL1R1(2q12-q13) and IL4R (16p12. 1) are considered OA risk factors (30-34). A genome-wide association scan identified that rs4140564 on chromosome 1 mapping 5' to both PTGS2 and PLA2G4A genes, promotes susceptibility to knee OA. Both of these genes are part of the prostaglandin E2(PGE2) synthesis pathway whose role will be mentioned in a subsequent section(35). COX2 (1q25), which encodes a cyclooxygenase, and ADAM12 (10q26.2), which encodes a metalloprotease, were reported to be associated with OA prevalence in a cohort of females(17).
3.4. Other loci variants
Allelic imbalances, such as a cis-regulated gene expression for TXNDC3 (encoding for Thioredoxin domain containing 3), RHOB (encoding for RHOB, a GTP-binding protein), and BLP2 (encoding for BBP-like protein 2), or trans-regulated gene expression of CIAS1 (encoding for Cold auto-inflammatory syndrome 1), showed a statistically significant association with OA(36). However, some investigators confirmed a negative association between RHOB and TXNDC3 genes with OA(37). Literature pertaining to the identification of the gene for the X-linked recessive form (Xp22.2) may explain the different incidence of OA according to sex(38,39). CD36 (7q21.11)(encoding for a thrombospondin and collagen receptor), NCOR2 (12q24.31)(encoding for a nuclear receptor co-repressor), EDG2 (a functional variant of lysophosphatidic acid G-protein-coupled receptor 2 gene), DIO2 (encoding type II iodothyronine deiodinase), SMAD3 (functions in TGF-beta signaling), PITX1 (transcription factor pituitary homeobox1), ACE (angiotensin-converting enzyme gene), and TNA (3p21.31)(encoding for tetranectin), were involved in OA prevalence and progression in females(17,40-44). The acidic leucine-rich nuclear phosphoprotein 32 family member A gene (ANP32A) encodes a tumor suppressor molecule involved in apoptosis and Wnt signaling, which is reported to be associated with hip OA in women(45). Furthermore, several loci are reported in (Table 1). Some chromosomes were frequently positive such as chromosome 2, 6, and 16. Animal models have been used to study the mechanisms of OA more fully in relation to human genetic mutations.
4. ANIMAL MODELS
Animal models include genetically modified and experimentally induced models that mimic OA pathogenetic mechanisms.
4.1. Genetically modified models
4.1.1. Factitious models
Many studies have exploited the availability of knockout or transgenic mouse models to address the roles of certain molecules in OA pathogenesis. It has been revealed that polymorphisms or mutations in genes encoding extracellular matrix genes and signaling molecules are associated with OA susceptibility (11,56). Thus, the loss or mutation of a single gene in a mouse model, such as Collagen IX (57,58), Col2a1, Col11a1, aggrecan, MT-1-MMP(59), alpha-1 integrin subunit (60), and ADAMTS5 (61) may lead to cartilage degeneration similar to that in OA patients. More specifically, the disruption of chondrocytes results in the interruption of the formation and remodeling of the cartilage matrix, such as the production of proteoglycans and aggrecan (62,63).
SLRPs are extracellular molecules that bind to TGF-betas, collagens, and other molecules. In vitro, SLRPs were shown to regulate collagen fibrillogenesis. Biglycan (BGN) and fibromodulin (FM) were two of the most prominent and widely expressed SLRPs. Cre-loxP sites flank the gene encoding BMP receptor type 1a (Bmpr1a). A promoter of the gene encoding growth differentiation factor 5 (Gdf5) is used to deplete this BMP receptor and direct cre-recombinase expression. Thus, Cre-Gdf5/Bmpr1afloxP mice are conditional knockout mice that are unable to produce BMP receptor type 1a selectively in developing joints(64). The BGN-deficient, FM-deficient, and BGN/FM double knockout, Cre-Gdf5/Bmpr1afloxP mice develop earlier and more severe osteoarthritis (61-67). Ptch1+/-, Col2A1-Gli2, COL2-rtTA-Cre, Gt(ROSA)26Sortm1(Smo/YFP)Am-transgenic mice were also chosen for the development of OA. Among these, the Col2A1-Gli2-transgenic mouse overexpressed the hedgehog (Hh)-activated transcription factor Gli2 under Col2A1 regulatory elements in chondrocytes. The Gt(ROSA)26Sortm1(Smo/YFP)Am-transgenic mouse expresses the constitutively active W539L point mutation of the SMO homolog protein (SmoM2) by Cre-mediated recombination. SmoM2 was expressed in chondrocytes when this mutant mouse was crossed with COL2-rtTA-Cre mice under doxycycline administration (68). Other mutant mice such as TNF transgenic mice develop a severe destructive arthritis, osteophyte, and subchondral bone stiffness. The relationship of human genetic mutations and animal genetic modification is documented in (Table 2).
4.1.2. Spontaneous models
Spontaneous models refer to certain breeds of animals that are genetically predisposed to OA and can develop symptoms at a relatively young age. In the laboratory, these models include rhesus macaques, dogs, guinea pigs, and mice. In some views, these models could be seen as genetic mutant species with unclear backgrounds.
The Rhesus monkey model is described to be particularly suitable for studying changes in cartilage collagen because the animal's long life span allows for the development of osteoarthritis over time. Morphological studies demonstrate that in these monkeys, as in humans, the disease is characterized by persistence of the chondrocyte density typified by an increase in (Ca) calcium, (P) phosphorus, (Mg) magnesium, (S) sulfur, (K) potassium, glycosaminoglycan (GAG) and collagen(69) in the cartilage of young animals(70). An epidemiological study showed increased incidence of OA disease with aging, and in females with increased parity. Therefore, these models are ideal because of the high prevalence rate, available age matched controls, and joints large enough for radiological and morphological studies. However, the drawbacks of using these big animals are their relatively long lifespan, uncontrolled environmental factors, ethic concerns, and the limitation of financial funding.
Immunologic reactivity has been observed with anti-type I, II collagen antibodies existing in sera and synovial fluids of dogs(71). Moreover, the changes in proteoglycan levels in the cartilage of the canine model were very similar to those observed for human OA cartilage(72). However, compared to human OA in the early phase of the disease, dogs display more serious changes in synovitis and joint capsule fibrosis.
Degenerative arthritis has been extensively studied in guinea pigs. The OA observed in this model has been found to have similar histologic, radiologic, and biochemical changes as those observed in human OA, such as breakdown of cartilage aggrecans(73), meniscal ossification(74), chondrocyte ATP depletion(75), and subchondral bone remodeling(76). Moreover, findings indicate that body mass in guinea pigs is an important predisposing factor for the development of spontaneous OA of the knee. There are several disadvantages pertaining to the guinea pig model. Some researchers observed the effect of matrix metalloproteinase inhibitors and ascorbic acid on OA from this spontaneous model (77-80). Also, OA progresses slowly in the guinea pig, which is not cost effective. Both of these reasons limit application and advancement of this particular model.
Recently, attention has been focused on small animals such as mice of STR/ORT, C57Bl/6, and BALB/c strains(81,82). Mice are utilized to examine cartilage degeneration(83), including loss of glycosaminoglycans in cartilage matrix, and type II collagen degradation(84), disturbed protein transport and sugar synthesis in chondrocytes, and irregularity of the free margin of the anterior segment of the meniscus. Nevertheless, cruciate ligament collagen metabolism is upregulated in this model(85). Additionally, it was observed that a horizontal cleft developed along the tidemark and eburnation of the subchondral bone(86). Moreover, the mice model also lacks morphological changes, such as fibrillation of the cartilage matrix, chondrocyte clustering, osteophyte formation or inflammation, possibly because of the animal's small joints and poor reparative ability. Smaller joints also instigate many other problems for investigators.
4.2. Experimentally induced models
Experimentally induced models evolved due to the demands of the research field. Previous reviews separated these models into monoarticular and polyarticular OA. However, monoarticular OA does not exist, because bilateral joints systemically or biomechanically interact, resulting in the bilateral articular OA.
4.2.1. Biomechanical factors
Biomechanical models of arthroses are of three types: surgical (intra-articular and extra-articular), immobilized, and overload.
Intra-articular surgical models usually induce instability of the joint. The original joint disease models developed historically were induced by patella dislocation(87) and patellectomies(88). However, these models showed severe erosive and proliferative lesions of the joint. As a result, less severe injury and more gradual degenerative progression were required for OA model creation. The Hulth-Telhag model is the classical OA model made by transecting the anterior and posterior cruciate ligaments and removing the meniscus. Degradation of type II collagen was seen as early as 3 weeks in this rabbit model(89). Recently, the popular surgical models are the anterior cruciate ligament transaction (ACLT) and the partial meniscectomy model(90,91). The combination of patella removal with ACLT could accelerate the occurrence of OA to approximately two weeks after the surgery, and further advance its development(92). Other methods such as tibial osteotomy(93), below-knee amputation, femur valgus osteotomy(94), or pelvic osteotomy(95), could also lead to degenerative arthritis. In these surgically-induced animal models, joint inflammation and repair were produced primarily in cartilage and synovium. One interesting surgical variant is the groove model made by Marijinissen. This model induces cartilage degeneration by one-time trauma (with features of OA at 10 weeks after induction), without causing synovial inflammation characteristic of the original model. This method increases the sensitivity of detecting defects of therapy aimed at cartilage protection and repair(96,97).
Extra-articular procedures which include ovariectomy(98), myomectomy(99) and tendonotomy(100) could also produce progressive OA. Ovariectomized models are useful for studying the effect of estrin and estrin-like substances on OA in postmenopausal women(98).
Immobilization models of OA were made in forced fixed position including flexed, intermediate, and extending posture. It was found that in both early and advanced OA, the synthesis rate of glycosaminoglycans and collagen increased, especially after half to one month, but the collagen content did not change(101). Moreover, a non-specific inflammatory cell response was rapidly induced in the synovial tissue in three days by abrasion(102). In the immobilization and subsequent remobilization experiment, plasma hyaluronate was maximally regulated shortly (45min) after splint removal(103). These studies elucidate the significance of joint motion.
Overload models include compression induction either without surgery or with excessive exercise. In the past, these models were combined with other methods to accelerate and aggravate the degenerative process(104,105). To initiate OA-like changes in an in vitro single-impact load model, a simple drop-tower device was used. This model would be valuable for understanding the early molecular pathways involved in the process(106,107).
4.2.2. Structural factor
In experimental structural OA models, tissue composition of one or more structural components of joints is degraded(105). Traditionally, structural OA models have been classified into groups (e.g. physical, chemical, and enzymatic) based on the selectivity of their action on target tissues or tissue components, such as collagen, proteoglycan, chondrocytes, or synoviocytes. Endocrine manipulation such as intra-articular corticosteroid administration, a high fat diet, or oral administration of quinolone analogues can promote the development of OA from a systemic view. These animal models help us to investigate the mechanisms of OA, especially at the cellular and molecular levels.
In physical alteration models, freezing, electrolysis, or ionizing radiation of articular cartilage may cause lesions in an anatomically discrete manner(108). Micromechanical models of surgical trauma induced by incision, shaving, abrasion or contusion perpetuate similar results(109-111). These models are useful to investigate the replication and matrix regeneration of chondrocytes. For example, defects that penetrate the subchondral bone could induce chondrocyte regeneration from reparative fibrocartilageinous calluses growing toward the marrow, while lesions that do not invade into subchondral bone usually fail to show this regeneration(112).
Chemical alteration refers to intra-articular administration of chemical agents such as heat, fixatives, protein denaturants, acids, alkalis, or ionic solutions to degrade the matrix and the superficial articular cartilage(105). Saline injection spawned synovial inflammation.
Currently, the most common technique used to generate models is enzymatic alterations. These models are created by proteolysis induced by the enzymes papain, trypsin, hyaluronidase, and collagenase(82). This model has been used to investigate broken collagen framework, synovial inflammation, cartilage proteoglycan depletion, chondrocyte necrosis, and ligament matrix injury and subsequently regeneration. Furthermore, intra-articular injection of cytotoxic drugs, including thiotepa, nitrogen mustard, colchicines, osmic acid, or iodoacetate directly damage articular cells. Indirect agents such as vitamin A and Filipin stimulate chondrocytes to produce and secrete matrix proteolytic enzymes by labializing cells and lysosome membranes(113). Sometimes, it's hard to differentiate between biochemical agents and chemical agents. Croton oil, carrageenin, zymosan, and dextran sulphate have been used to induce degenerative arthritis. However, changes in these models are complex. For instance, specific biological mediators such as IL-1/OSM, TNF, and TGF-beta2 may be intra-articularly injected. IL-1 has a more direct inhibitory effect on proteoglycan synthesis, which is mediated by metalloproteinases(114). Ectogenous TGF-beta2 induces synovial fluid, synovial cells hyperplasia, cartilage edema, and proteoglycan degradation. Moreover, synovitis observation requires the application of magnesium tetrasilicate, or talcum powder, via intra-articular injection. These models provide an opportunity to study the effect of endogenous factors on the progression of OA.
5. MECHANISMS
5.1. Cellular changes
Damage resulting from OA can be observed in the three components that constitute a joint: articular cartilage, subchondral bone, and/or synovium. The degree of pathological changes in OA is determined by the aforementioned factors(115).
Articular cartilage is unvascularized, aneural, and full of ECM, which is mainly composed of water, type II collagen, and proteoglycan aggrecan(116). Other components have been identified in the matrix, such as type IX and XI collagen, cartilage oligomeric matrix protein, matrilin-3, decorin, biglycan, and fibromodulin(117). Chondrocytes are another important component of cartilage. Chondrocytes are encapsulated within a lacuna, which hinders their ability to migrate to the site of injury. Thus, chondrocytes do not have the capacity for renewal, proliferation, or repair(118). In normal cartilage, there are four zones of chondrocytes: resting cells orientating within the collagen fibers in the superficial zone, large and randomly distributed cells in the middle zone, columns of chondrocytes in the deep zone, and hypertrophic cells in the calcified zone(116).
The pathological changes of OA in articular cartilage are less anabolic and more catabolic, such as the loss of ECM and cell apoptosis. Cartilage matrix degradation products like type II collagen, proteoglycans, and fibronectin seemed to aggravate cartilage destruction with the fibrils at the articular surface(119). When OA occurs and proceeds, the regular cellular populations change into one of three types. The first type of cellular population is singular and clustered. The second type is elongated and secretory like fibro-chondrocytes or other dedifferentiated phenotypes, which express several proteins such as biglycan, decorin, perlecan, and type I and X collagen to form repaired fibrocartilage(120,121). The last type is irregularly shaped cells such as those that undergo pyknosis. The thinning of the soft articular surface accompanied with the thickening of the hypertrophy chondrocytes layer lead to upward shift of the tidemark between articular and calcified cartilage(122). Neovascularisation was found to break the tidemark through microcracks and fissures that occur in the cartilage, which seems to produce mesenchymal stem cells (MSCs) or bone progenitor cells like the second type of cells previously mentioned(123). Features of OA in the subchondral bone are fibrillation, sclerosis, even collapse, together with bone cysts, thickened cortical plate, extensive remodeled trabeculae and osteophyte formation surrounding articular margins(115,124,125). Increase in subchondral bone stiffness are considered as an adaptation to changes in the biomechanics of the joint, but it simultaneously limits the strain in the articular cartilage(122).
Osteoclasts also play a crucial role in the process of OA. In OA-like lesions in the mandibular condyle of rat, osteoclastogeneis occurred by increased osteoclast numbers and proportion of surface area in the subchondral bone regions(126). The subchondral bone plate could be thinning 4 weeks after instability-, collagenase-induced OA, with osteoclasts observed underneath it(127).
There are three types of synovial lining cells within the superior and middle layers: macrophages, fibroblasts, and undifferentiated precursors. The deep layer includes adipose, fibrous, and areolar tissue. Synovial fluid is produced by fibroblasts in the synovium, and is considered an ultrafiltrate of plasma because of the presence of hyaluronate and lubricin(128). In the normal state, nutrients in the synovial fluid and cellular repair components are diffused within the cartilage. In OA, synovial fibers thicken and more pro-inflammatory mediators arise in the synovial liquid. There is also evidence that activated T-cells, B-cells, and macrophages infiltrate the synovium in OA (129). However, mature and activated osteoclasts could not found in the OA synovium(130).
Thus, OA is distinguished by the following features: thin, fibrillated articular cartilage, reduced joint space, thickened capsule, and angiogenesis with possible innervation, synovitis, subchondral bone sclerosis, and osteophytes at joint margins (131).
5.2. Molecular changes
Many cytokines and growth factors, some of which participate in cartilage development, are produced by the synovial fibroblasts, chondrocytes, osteoblasts and osteoclasts in OA.
Synthesis of catabolic factors, such as matrix metalloproteinases (MMPs), membrane-type I MMP, MMP-1,3,8,9,13,14 and the aggrecanase protein ADAMTS1,4 and 5, is increased (59,74,118,132-135) and synthesis of their inhibitors such as TIMP is decreased by pro- or inflammatory cytokines like interleukin IL-1, IL-6, IL-17 and IL-18, TNF-alpha(136-139), nitric oxide (NO), PGE2, COX-2, and netrins along with their receptors(140). Some chemokines including CC-chemokine ligand-5 (CCL5), IL-8, growth-related oncogene-α (GROα) and monocyte chemotactic protein (MCP-1) are also elevated in OA tissues to induce inducible nitric oxide synthase (iNOS), MMP-1, IL-6 and stimulate proteoglycan depletion(141). However, some of these factors such as MMP-1 also show opposite changes depending upon the severity of OA(142). Recently, it was demonstrated that the signaling pathway of shear-induced IL-6 expression is related to the roles of E prostanoid (EP)2 and EP3 in cAMP/protein kinase A- and PI3-K/Akt-dependent NF-kappaB activation(143). Cathepsin K, TRAP, and osteocalcin mRNA levels were raised in the intertrochanteric region of the proximal femur of OA patient with femoral neck fracture(144). Besides cathepsin K, cathepsin B, L from the chondrocytes play a role in further cartilage destruction with the local fallen pH value of the cartilage(145). Moreover, nuclear factor of activated T cells 2 (nfat2), osteoclast-associated receptor (oscar), and alkaline phosphatase (ALP) mRNA expressions were found to be enhanced in the synovial fluid of OA patient (146).
Anabolic factors such as insulin-like growth factor (IGF-1), TGF-beta, connective tissue growth factor (CTGF), fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), OPG/ receptor activator of NF-kappaB ligand (RANKL), and BMPs either decrease or increase proceeding reaction with damaged spatiotemporal variations(147-149). Additionally, some neuropeptides like substance P, corticotropin-releasing factor, urocortin, and vasoactive intestinal peptide may also be involved in OA development(150,151). In RANKL- and TNF-induced OA, increasing NF-kappaB p100 protein and TNF receptor-associated factor 3 (TRAF3) accumulations in osteoclast precursors (OCPs) could limit bone destruction, indicating an anabolic effect for these two proteins(152). Anti-inflammatory cytokines including IL-4,10,13 etc play a role in inhibiting IL-1beta, TNF and proteases, upregulating IL-1Ra and TIMP production(153).
Senescence markers such as senescence-associated enzyme beta-galactosidase (SA-betagal), p53, p21, p16, superoxide dismutase 2 (SOD2), reactive oxygen species (ROS) and telomere shortening are also exhibited in OA(154). However, the function of these factors is complex. For example, a reduction in SOD2 has been reported to be associated with an increase in ROS in the earliest stages of OA, but also with a reduction of collagenase gene expression(153). Moreover, these findings pose difficulties in distinguishing age-related changes from OA.
Nowadays, more and more novel initiators of OA have being found such as transmembrane serine proteinase matriptase in cartilage destruction, which activates selective proMMPs and induces collagenase expression(155). HIF-2alpha, induced by NF-kappaB, is crucial for endochondral ossification(7). Three of the autophagy-related factors, Unc-51-like kinase 1 (ULK1), Beclin1, and microtubule-associated protein 1 light chain 3 (LC3), showed a reduction or loss of expression in the development of OA(156). The cytokine levels in OA have been reviewed in detail (157). These biochemical substances interact and contribute to cellular changes. Several cytokines, such as inflammatory factors(158), and the Wnt signaling pathway(159), have been widely reviewed. Therefore, the focus in this paper is on BMPs, and the molecules mentioned above or in other reviews would be summarized in Figure 1.
5.3. BMPs
BMP-2 is present in chondrocytes during neonatal growth of articular cartilage, but is scarcely expressed in normal adult articular cartilage. However, the BMP gene has been genetically linked to OA.
5.3.1. BMPs and articular cartilage
BMP-2 mRNA and protein were found in both clustering and individual chondrocytes in moderately or severely damaged OA cartilage. In moderately damaged OA cartilage, cellular localization of BMP-2 mRNA was limited in both upper and middle zone chondrocytes. In severely damaged OA cartilage, it extended to the deep zone chondrocytes(160). Phosphorylation of Smad-1, Smad-5, the downstream of BMP-2, were upregulated, meanwhile Smad-2 and -3 were degraded in a Smurf2-dependent manner in OA conditions(161,162). In a posttraumatic OA (PTA) model generated by a single high-energy impact load, proteoglycan loss was detected along with decreased BMP-2, indicating that BMP-2 may participate in PG synthesis(107). Furthermore, chondrocytes overexpressing BMP-2 showed increased aggrecan synthesis(163). On the other hand, genetic variation in BMP receptor signaling may be involved in human OA development(64, 164).
Asporin, an extracellular matrix protein up-regulated in disease states, binds to BMP-2 and negatively regulates its activity(165). The actin-binding protein calponin 3, which interacts with Smad-1 and -5, was reduced in OA cartilage. Since calponin 3 provides a negative regulatory mechanism for the BMP signaling pathway, its down-regulation could contribute to the increase of BMP-2 expression in OA joints(166). Noggin is one of the BMP binding proteins, and it acts as an antagonist. Noggin null mice exhibit defects in joint morphogenesis, indicating that the overexpression of BMPs plays a critical role in OA pathogenesis(167). Chordin is another antagonist of BMP. It was found not only in the superficial layers in normal cartilage, but also at a significantly higher level in the last two thirds of the OA cartilage. However, the mRNA and protein levels of chordin were downregulated in OA(168).
It has been reported that Smad3 knockout (TGF-beta deficient) mice display OA phenotypes. The gene profiling and PCR examination showed that BMP signaling pathways involving Smad-1, Smad-5, BMP-2, and BMP-6, were more active in Smad3 knockout chondrocytes(169), suggesting a shift from TGF-beta toward BMP signaling. Thus, as an extracellular BMP inhibitor, noggin could abrogate its maturation (170). In vitro and in vivo OA models demonstrated that BMP-2 induced growth arrest and DNA damage, stimulated (GADD)45beta transcription factor depending on the suppression of COL2A1 by NF-kappaB, and upregulated matrix meatalloproteinase-13 (MMP-13) expression(171). Up-regulation of BMP-2 might be caused by pro-inflammatory cytokines IL-1beta and TNF-alpha (but not TGF-beta and IGF-1), which are known to be present in synovium and cartilage of patients with OA(172,173).
BMP-7 is considered an anabolic mediator. It may stimulate superficial zone protein, function as a key mediator of boundary lubrication of articular cartilage in joints, and it may also improve damaged intra-articular tissues by synthesizing and secreting chondrogenically differentiated infrapatellar fat pad (IFP) progenitor cells. These functions indicate that BMP-7 would potentially be a useful source for inducing superficial zone of articular cartilage(174). Furthermore, it generally had a more significant stimulatory effect in cultures of immature bovine cartilage explants than in cultures of mature explants(175).
Human meniscus cells, which came from meniscectomy of the knee joint in individuals with OA, also expressed BMP-2, and -4. These cells were stained with AS.02, which recognizes a protein on human fibroblasts that is highly homologous or identical to human Thy-1 antigen (CD90), which is one of the markers for mesenchymal stem cells (MSCs). These findings suggest a mesenchymal origin of human meniscus cells(176).
5.3.2. BMPs and subchondral bone
Interestingly, OA osteoblast mineralization in tibial plateaus was less than that of normal osteoblasts, even in the presence of BMP-2(177). The vascular invasion of bone marrow tissue into the subchondral plate was observed in articular cartilage in OA patients, who also expressed BMP-2 and -4 in reparative levels(178).
5.3.3. BMPs and synovium
In the collagenase-induced OA model, BMP-2 and -4 are strongly expressed in deeper layers of the synovium, periosteum, and lining. Presence of BMP-2 and -4 in the lining is induced by synovial macrophages(179). On the other hand, overexpression of Smad-6 and -7, two BMP antagonists, caused a reduction in synovial thickening, indicating that BMPs are also involved in this process(180). Mechanical load would be one of the factors that stimulate BMPs. For example, exposure of synovial fibroblasts (SFs) of the rat temporomandibular joint (TMJ) to hydrostatic pressure (HP) causes significant up-regulation of BMP-2, which may influence pathological conditions, such as temporomandibular disorders(181). However, BMP-2 alone in vitro hardly induces chondrogenic differentiation of synovium-derived stromal cells; however, it can induce chondrogenesis and synthesis of cartilage-like matrix when combined with TGF-beta1(182).
The expression of BMP-4 and BMP-5 expression decreases in synovial tissue of OA patients, and their distribution varies within the lining and sublining of the layer(183). Levels of BMP-7 are found to increase in both plasma and synovial fluid of OA patients. Conclusively, there exists a positive correlation between BMP levels and OA: overexpression of BMP-7 in plasma and synovial fluid is associated with OA development(184).
5.3.4. BMPs and repair
Osteophyte formation is considered a repair process of bone. BMP-2 induced early osteophytes, which bulged from the growth plates on the femur and grew on top of the patella. Moreover, BMP-2 was strongly expressed in the late-stage osteophytes in STR/ort and collagenase-induced models(185). Other scientists found that BMP-2 mRNA was most prominently localized in fibroblastic mesenchymal cells, fibrochondrocytes, chondrocytes, and osteoblasts in newly formed osteophytes(160). This osteophyte formation could be completely blocked by Ad-Gremlin and significantly reduced by Smad-6 and -7(180). However, this osteophyte formation is different from those induced by TGF-beta and experimental OA(82).
BMP-2 has been proposed as a tool for cartilage repair and as a stimulant of chondrogenesis. In healthy cartilage, BMP-2 is hardly present, whereas it is highly expressed in cartilage of OA individuals. When BMP-2 was overexpressed in healthy murine knee joints, PG synthesis, aggrecan mRNA expression, collagen type II expression, and aggrecan degradation increased in patellar and tibial cartilage. BMP-2 boosts matrix turnover not only in intact but also in IL-damaged cartilage. Thus, BMP-2 contributes to the intrinsic repair capacity of damaged cartilage matrix(186). This may be related to increasing TIMP-1 production(187). Chondrocyte or stem cell transplantation with cells expressing BMP-2 may improve cartilage repair(188).
In vivo, skeletal muscle-derived stem cells (MDSCs) expressing sFlt-1(one of the VEGF antagonists) and BMP-4 demonstrated better repair without osteophyte formation, higher differentiation/proliferation, and lower levels of chondrocyte apoptosis in the OA model. In vitro, coculture of BMP-4-transduced MDSCs and OA chondrocytes produced the highest gene expression of type II collagen, and SOX9, as well as type X collagen, suggesting terminal differentiation of chondrocytes(189). In the OA rat model produced by excessive running or ACLT, periodical injections of BMP-7 could delay the cartilage degeneration (91,190). Furthermore, BMP-7 may be chondroprotective after traumatic injury in patients via an increased survival of chondrocytes, which is evidenced by stimulating proteoglycan synthesis to participate in the repair process(191-193).
Others involved in potential prevention of OA include HrtA1 (high-temperature requirement protein A1), programmable cell of monocytic origin (PCMO), and Periodontal ligament-associated protein-1 (PLAP-1)/asporin. HrtA1 is a key regulator of physiological and pathological matrix mineralization in vitro, which is proposed to be related to TGF-beta/BMP signaling inhibition(194). PCMO is a new adult pluripotent cell derived from human peripheral blood monocytes. After 6 weeks of stimulation with BMP-2 and BMP-7, PCMO have the potential to differentiate into chondrocytes by producing collagen type II(195). PLAP-1/asporin is a member of the small leucine-rich repeat proteoglycan family, which has been proven to be a negative regulator of mineralization most understandably by regulating BMP-2 activity involved in ankylosis prevention(196).
5.3.5. Others
Microarray expression profiling of osteoarthritic bone suggested altered bone remodeling and revealed many genes that are differentially expressed. Many of these genes are targets of either the WNT (wingless MMTV integration) signalling pathway (TWIST1, IBSP, S100A4, MMP25, RUNX2 and CD14) or the transforming growth factor (TGF)-beta/bone morphogenic protein (BMP) signalling pathway (ADAMTS4, ADM, MEPE, GADD45B, COL4A1 and FST). Other differentially expressed genes included WNT (WNT5B, NHERF1, CTNNB1 and PTEN) and TGF-beta/BMP (TGFB1, SMAD3, BMP5 and INHBA) signalling pathway component or modulating genes. In addition, a subset of genes was identified to be differentially expressed in OA between males and females such as GSN, PTK9, VCAM1, ITGB2, ANXA2, GRN, PDE4A and FOXP1, which were involved in osteoclast function(197).
At the present time, several therapies for OA have been used clinically and pre-clinically besides cytokines, such as BMPs. However, clinical efficacy is the gold criterion for evaluating the quality of therapy. Of course, the side effects, difficulties of execution, and level of grief for the patients are also taken into consideration. The effects of the treatment regarding pain relief and functional improvement are usually evaluated clinically for OA treatment.
6. THERAPIES
Current therapeutic strategies for OA include clinical and preclinical procedures.
6.1. Clinical therapy
A comparison of the clinical therapies available for OA patients is provided below and in Table 4.
6.1.1. Global treatments
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most popular therapy for OA, due to their effectiveness in relieving pain and improving function. These drugs significantly reduced PGE2 and downregulated COX-2 in the synovium and cartilage(198,199). However, NSAIDs are associated with significant adverse effects on the integrity of the gastrointestinal (GI) mucosa and on the cardiovascular system(200). The countermeasures for these side-effects include concomitant use of gastric-protective medicine such as misoprostol, a PGE1 analog(201), using an enteric coated formulation(200), improving health-related quality of life(202), or changing administration routine as mentioned in the section titled "External applied agent". Nowadays, new lower-risk NSAIDs are available, but at a greater monetary value.
Non-opioid analgesics, such as acetaminophen, also known as paracetamol or Tylenol, is equally effective at achieving relief of mild to moderate joint pain as NSAIDs(203,204). However, NSAIDs appear to be more effective at relieving moderate to severe pain. A study including fifteen randomized controlled trials (RCTs) and 5986 participants demonstrated no significant difference between the safety of acetaminophen and NSAIDs(205), although previous meta-analysis indicated this compound was safer and should be the first line of treatment(206). Acetaminophen should be used cautiously in patients with liver defects and those who chronically abuse alcohol (207-209). Other drugs like tramadol could be used in patients in whom acetaminophen therapy has failed (210). When NSAIDS and non-opioid analgesics have no significant effect, opioid therapy (211) may be considered. However, tolerance, dependence, and other adverse effects may be not avoided while using this treatment.
Acupuncture & Traditional Chinese medicine may also be effective as treatment for OA. A systematic review of seven trials employing a total of 393 patients with knee OA revealed real acupuncture is more effective in pain relief than needles placed at non-acupuncture points on the body. However, real acupuncture has not conclusively shown better effects in functional improvement. Furthermore, the comparison of efficacy of acupuncture with other treatments need more evidence(212,213). Some Traditional Chinese medicines have been reported to be safe, tolerable, and effective for symptomatic improvement of pain and physical function, such as willow bark extract, ginger extract, boswellia-curcuma mixture, avocado-soybean unsaponifiables (americana Glycine max), boswellia serrata gum resine extract, cat's claw extract, arnica tincture, comfrey extract, Tipi tea, stinging nettle leaf, the Chinese herbal mixture SKI306X, Duhuo Jisheng Wan (214,215), and a seaweed extract nutrient complex(216). Recently, it has been reported that human placenta extract (HPE) suppressed the histological changes in monoiodoacetate (MIA)-induced OA by inhibiting PG degradation and MMP-2 activity and that HPE may reduce deformity of knee joints (217). Other treatments such as exercise, Tai Chi, bracing and corrective footwear, pale vitamin E, behavioral interventions, spa, pulsed signal therapy, and hyperthermia have been shown to improve OA(4, 145, 218-224).
6.1.2. Local treatments
Glucosamine and chondroitin naturally exist in the body to repair and maintain cartilage. These natural supplements have become popularized because of their safety and their effectiveness in relieving arthritis symptoms(225). Two RCTs, proceeded by a follow-up of 8 years, showed that treatment with glucosamine sulphate for 1 to 3 years may prevent total joint replacement for an average of 5 years after drug discontinuation(226). These compounds are absorbed through the gastrointestinal tract and are able to increase proteoglycan synthesis in articular cartilage(227,228). Animal experiments showed oral glucosamine sulfate not only attenuates the development of OA, but also reduces nociception and modulates chondrocyte metabolism. The mechanism would be related to mitogen-activated protein kinases (MAPKs), by inhibiting cell p38 and c-Jun N-terminal kinase (JNK) and increasing extracellular signal-regulated kinase 1/2 (ERK) expression(229). Chondroitin sulfate may reduce degradation of cartilage collagen and proteoglycans by partially inhibiting leukocyte elastase(230,231). However, recent meta-analysis found that chondroitin has minimal or insignificant benefits for OA symptomology(232). A meta-analysis of 15 RCTs of glucosamine and chondroitin compounds showed that all but one of these trials were classified as positive(219). Moreover the effects were greater for chondroitin than for glucosamine. Further studies are highly suggested to assess the relationship between time, dose, patient baseline characteristics, and structural efficacy; moreover, these studies may provide an accurate, disease-modifying characterization and a biological mechanism of these two compounds (233-235). It has been recently reported that undenatured type II collagen (UC-II) at a dose of 480 or 640 mg was more effective than glucosamine and chondroitin in arthritic horses and that it was tolerated well (236). However, it still needs clinical evidence. Other related compounds such as sodium hyaluronate and undenatured type II collagen have been reported to be efficacious in the treatment of knee OA(237,238). However, in a recent, multicentre, randomized, placebo-controlled, double-blind study of 337 patients followed for 1 year there was no clinical effect of intra-articular hyaluronan was shown(239).
Only 5% of OA patients need surgical treatment when conservative treatment displays no satisfactory effect. There are four categories of surgical procedures: osteotomy, arthroscopy, arthrodesis, and arthroplasty.
The purpose of the osteotomy is to transfer the load bearing from the pathologic to the normal compartments of the knee. Thirteen studies involving over 693 people indicated that valgus high tibial osteotomy is effective in improving knee function and relief of pain. However, it is uncertain which treatment, osteotomies or conservative treatment is more effective(240). Furthermore, a successful result of the osteotomy (about 60.3%) depends on proper patient selection, stage of osteoarthritis, and achievement and maintenance of adequate operative correction(241).
Arthroscopy is an alternative procedure to osteotomy(242). It is not only useful for the treatment of the same symptoms, but also for diagnosis of the disease. Although arthroscopic methods are widely used, they are not suitable for patients who have displayed OA symptoms for more than 2 years, or who display tibial osteophytes and joint space narrowing of less than 5mm (4 or more of these factors)(243). Arthroscopy is effective only temporarily in reducing the pain of mild to moderate hip OA(244).
Arthrodesis is an efficient procedure for OA of the hands, feet, ankles, and spine, but usually not for the hip and knees(245-248). In arthrodesis, multiple Kirschner wires, cannulated screwsiliac, and crest bone graft are frequently utilized to reduce nonunion rates(249).
Arthroplasty refers to the insertion of an artificial joint in order to restore the integrity and the function of the joint withered by OA. Joints commonly deteriorate after more than ten years, depending on the composition(250). The perioperative morbidity of unicompartmental knee arthroplasty would be less than total knee arthroplasty; furthermore, this arthroplasty has been reported to be used in very elderly patients (79-94 years) with tricompartment OA. Therefore, age is not a limiting factor for this surgical treatment(251).
Use of local topical analgesics, such as capsaicin cream and NSAID gel (eltenac), function as either an adjunctive treatment or monotherapy for pain relief in OA patients(252, 253). These treatments have low incidence of local skin reactions, such as local burning sensations.
6.2. Preclinical therapy
Preclinical therapy is proven only effective in animals or cells, and marginally in clinical cases.
6.2.1. Anticytokine/cytokine therapy
Anticytokine therapy targets the activity of catabolic cytokines, including proteinases, cytokine-induced signaling pathways, inflammatory factors (statin, recombinant IL-1Ra as anakinra), monoclonal anti-TNF antibody (adalimumab, infliximab), iNOS inhibitors SD-6010, MMP inhibitor PG-116800, cathepsin K inhibitor SB-553484(254-258), and chondrocyte apoptosis related to cytokines(259,260). Some growth factors, such as TGF-beta, BMP-7 and FGF-18, are perhaps effective in improving OA. Recently, an angiogenesis inhibitor thrombospondin-1 (TSP-1) has been reported to be intraarticular transferred and to inhibit OA development, probably by inducing TGF-beta production and by reducing microvessel density, macrophage infiltration, and IL-1 beta levels(261). Tanezumab, a humanized monoclonal antibody that inhibits nerve growth factor has been reported to reduce joint pain and improve function of patients with moderate-to-severe knee OA(262). However, these factors may be secreted from multiple cell types at different phases of OA, causing difficulties in their application.
Other anticytokines, such as the kinin B2 receptor antagonists, MEN16132, and icatibant are helpful for reducing pain, as evidenced in the monosodium iodoacetate-induced OA model(263). The highly selective A(3) adenosine receptor agonist CF101 was described as a cartilage protective agent by inducing apoptosis of inflammatory cells via deregulating the NF-kappaB signaling pathway(264). Calcitonin could promote matrix synthesis of chondocytes and inhibit cartilage degradation, which may involve in attenuation of MMP activity(265). Subcutaneous or intranasal administration of calcitonin has been shown to have effects on inhibition of bone resorption by binding to the calcitonin receptors on osteoclasts(266).
Since the equilibrium between OPG and RANKL plays a role in the pathology of OA, this system was expected as a new strategy for OA treatment(267).
6.2.2. Gene therapy
OA has a surprising degree of heritability and multiple interacting loci; thereby, much progress has been made to genetically modify synovium, cartilaginous matrix(268,269). However, the successful modification of relevant gene mutations that are associated with OA seems impossible to accomplish in the near future. Nonetheless, gene therapy is believed to be a powerful tool in gene modification techniques.
6.2.3. Tissue/Cell transplantation
In 1994, Brittberg et al. introduced autologous chondrocyte implantation. However, due to articular cartilage defects exhibited in OA patients, usage of this technique poses some difficulty. Recently, several researchers are attempting to treat OA by tissue-engineering methods, which are based on stem cells and scaffolds, but not on chondrocytes (270). Ideally, the most effective approach is to combine these methods to promote cartilage regeneration and inhibit destruction(271).
7. SUMMARY AND FUTURE DIRECTIONS
Although several genes have been found to be associated with OA, genetic epidemiology demonstrates that these genes rarely undergo mutation, are limited to the human species and demographic location of these species, and do not have a sufficiently high frequency to confer significant population risks of primary OA(272). Moreover, molecular studies of larger cohorts may be required to yield more conclusive results concerning the genetic factors of OA and to exclude false positives. Table 2 lists several target genes recommended for further validation and study in animal models.
No consensus currently exists regarding which animal model is most relevant to the study of OA. Each model offers advantages and disadvantages (Table 3). Genetically modified mice are the best tools for mechanistic studies aimed at understanding the functional role of specific molecules in OA pathology; still some reservations remain concerning the mouse model, particularly their physiological relevance to the human disease, and their use as drug-screening tools. Furthermore, mouse models are also time-consuming and expensive, and they require cooperation between researchers in different fields. Spontaneous OA models are less affected by external factors such as these, so the consequences resulting from manipulation could be eliminated. These models are beneficial in studying the primary onset of OA, biochemical changes of articular cartilage, prevention and treatment, and the causation in several physiopathological changes. However, similar to the factitious models, they are time-consuming, and more individual differences exist in the progression of the disease (as in humans). Surgically induced models develop rapid and reproducible damage. They are especially useful for studying anti-inflammation and cartilage protection. However, these models are not suitable for observation of biochemical and metabolic changes associated with the progression of OA because surgical trauma and inflammation may have an affect. Intra-articular administration of agents may generate models in little time, and can mimic the final step of cartilage injury. Thus, these models are valuable for investigating cartilage pathology and the therapeutic effect of drugs. Despite this, agent-dose should be monitored in the joints of different OA models. Clearly, the biochemical and structural models of OA are complementary. In practice, they are usually combined. The utilization of several species increases the number of models available. However, the discrepancies in the animal size, lifespan, disease progression, and response to treatment should be taken into consideration.
So far, the mechanisms of OA development seem clear both at the gross anatomical and the molecular levels. However, the global effects, such as the connection between individual molecules, have been modestly revealed. Even single cytokine families, such as the BMPs, play different roles in different phases of OA. These varying effects present more difficulties when studying signaling crosstalk. It is of great necessity to discover the precise actions and interactions of these cytokines in further studies. Interestingly, studies have suggested that rheumatoid arthritis and OA share some common characteristics (264).
In this review, we use the gold criterion to elevate therapeutic effect. However, the clinical trials in meta-analysis usually only measured the symptoms, which might omit the effect of therapies on the pathological progression of OA. Furthermore, larger cohorts of patients for longer time periods are needed to verify the usefulness of these therapies. In the future, preclinical therapies call for more validation and application. For example, replacing OA tissues with ideal scaffolds, introducing proper stem/progenitor cells, creating a suitable microenvironment for their function, and rehabilitating the function of the regenerated tissues, is recommended for future exploration. Moreover, it takes a long lead-time for the development of OA, therefore, the structural failure might begin several years before symptoms appearance. So preventive treatments could be used in adult populations (273).
8. ACKNOWLEDGMENTS
We thank Christie Paulson for her assistance with the manuscript. This work was supported by National Basic Research Program in China (973 Plan, 2010CB530400, Yong-jun Wang), Youth Health research project (2009Y092, Qin Bian), the National Natural Foundation Committee (NSFC) of China key grant (30930111, Yong-jun Wang), and National Institutes of Health (NIH) Grants AR-44741 (to Y.-P. L.), and AR-055307 (to Y.-P. L.).
9. REFERENCES
1. Bitton, Ryan: The economic burden of osteoarthritis. Am J Manag Care 15, S230-S235 (2009)
2. March, Lynette M., Bagga, Hanish: Epidemiology of osteoarthritis in Australia. Med J Aust 180, S6-S10 (2004)
3. Sinkov, Vladamir, Cymet, Tyler: Osteoarthritis: understanding the pathophysiology, genetics, and treatments. J Natl Med Assoc 95, 475-482 (2003)
PMid:12856913 PMCid:2594535
4. Williams, Charlene J., Rock, Matthew, Considine, Eileen, McCarron, Seamus, Gow, Peter, Ladda, Roger, McLaln, David, Michels, Virginia M., Murphy, William, Prockop, Darwin J., Ganguly, Arupa: Three new point mutations in type II procollagen (COL2A1) and identification of a 4th family with the COL2A1 Arg519→Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet 4, 309-312 (1995)
doi:10.1093/hmg/4.2.309
PMid:7757086
5. Holderbaum, Daniel, Bleasel, J. F., Jonsson, H., Saxne, T., Prockop, D. J., Williams, C. J., Moskowitz, R. W.: Arg519-Cys-associated haplotype in Icelandic family suggests early origin of this mutation. Matrix Biol 15, 178 (1996)
doi:10.1016/S0945-053X(96)90066-9
6. Saito, Taku, Fukai, Atsushi, MabuchiAkihiko, Ikeda, Toshiyuki, Yano, Fumiko, Ohba, Shinsuke, Nishida, Nao, Akune, Toru, Yoshimura, Noriko, Nakagawa, Takumi, Nakamura, Kozo, Tokunaga, Katsushi, Chung, Ung-il, Kawaguchi, Hiroshi: Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 16, 678-686 (2010)
doi:10.1038/nm.2146
PMid:20495570
7. Vikkula, Miikka, Mariman, Edwin C. M., Lui, Vincent C. H., Zhidkova, Natalia I., Tiller, George E., Goldring, Mary B., van Beersum, Sylvia E. C., de Waal Malefijt, Maarten C., van den Hoogen, Frank H. J., Ropers, Hans-Hilger, Mayne, Richard, Cheah, Kathryn S. E., Olsen, Bjorn R., Warman, Matthew L., Brunner, Han G.: Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80, 431-437 (1995)
PMid:16080123
8. Gleghorn, Lindsay, Ramesar, Rajkumar, Beighton, Peter, Wallis, Gillian: A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe. Am J Hum Genet 77, 484-490 (2005)
doi:10.1086/444401
PMid:15640800
9. Kizawa, Hideki, Kou, Ikuyo, Iida, Aritoshi, Sudo, Akihiro, Miyamoto, Yoshinari, Fukuda, Akira, Mabuchi, Akihiko, Kotani, Akihiro, Kawakami, Akira, Yamamoto, Seizo, Uchida, Atsumasa, Nakamura, Kozo, Notoya, Kohei, Nakamura, Yusuke, Ikegawa, Shiro: An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 37, 138-144 (2005)
doi:10.1038/ng1496
10. Valdes, Ana M., Loughlin, John, Oene, Mark Van, Chapman, Kay, Surdulescu, Gabriela L., Doherty, Michael, Spector, Tim D.: Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum 56, 137-146 (2007)
doi:10.1002/art.22301
PMid:17517696
11. Nakamura, Takahiro, Shi, Dongquan, Tzetis, Maria, Rodriguez-Lopez, Julio, Miyamoto, Yoshinari, Tsezou, Aspasia, Gonzalez, Antonio, Jiang, Qing, Kamatani, Naoyuki, Loughlin, John, Ikegawa, Shiro: Meta-analysis of association between the ASPN D-repeat and osteoarthritis. Hum Mol Genet 16, 1676-1681 (2007)
doi:10.1093/hmg/ddm115
PMid:18304494 PMCid:2427233
12. Song, You-Qiang, Cheung, Kenneth M., Ho, Daniel W., Poon, Sandy C., Chiba, Kazuhiro, Kawaguchi, Yoshiharu, Hirose, Yuichiro, Alini, Mauro, Grad, Sibylle, Yee, Anita F., Leong, John C., Luk, Keith D., Yip, Shea-Ping, Karppinen, Jaro, Cheah, Kathryn S., Sham, Pak, Ikegawa, Shiro, Chan, Danny: Association of the Asporin D14 Allele with Lumbar-Disc Degeneration in Asians. Am J Hum Genet 82, 744-747 (2008)
doi:10.1016/j.ajhg.2007.12.017
13. Paassilta, Petteri, Lohiniva, Jaana, Annunen, Susanna, Bonaventure, Jacky, Le Merrer, Martine, Pai, Lori, Ala-Kokko, Leena: COL9A3: A third locus for multiple epiphyseal dysplasia. Am J Hum Genet 64, 1036-1044 (1999)
doi:10.1086/302328
PMid:12736871
14. Stefánsson, Stefan Einar, Jónsson, Helgi, Ingvarsson, Thorvaldur, Manolescu, Ileana, Jónsson, Hjortur H., Olafsdóttir, Guebjorg, Pálsdóttir, Ebba, Stefánsdóttir, Gereur, Sveinbjörnsdóttir, Guefinna, Frigge, Michael L., Kong, Augustine, Gulcher, Jeffrey R., Stefansson1, Kari: Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet 72, 1448-1459 (2003)
doi:10.1086/375556
PMid:15210948 PMCid:470747
15. Loughlin, John, Dowling, Barbara, Chapman, Kay, Marcelline, Lucy, Mustafa, Zehra, Southam, Lorraine, Ferreira, Athena, Ciesielski, Cathleen, Carson, Dennis A., Corr, Maripat: Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U. S. A.101, 9757-9762 (2004)
doi:10.1073/pnas.0403456101
16. Valdes, Ana M., Hart, Deborah J., Jones, Karen A., Surdulescu, Gabriela, Swarbrick, Peter, Doyle, David V., Schafer, Alan J., Spector, Tim D.: Association study of candidate genes for the prevalence and progression of knee osteoarthritis. Arthritis Rheum 50, 2497-2507 (2004)
doi:10.1002/art.20443
PMid:9218501 PMCid:508187
17. Uitterlinden, Andre G., Burger, Huibert, Huang, Qiuju, Odding, Else, Duijn, Cornelia M. van, Hofman, Albert, Birkenhäger, Jan C., van Leeuwen, Johannes P. T. M., Pols, Huibert A. P.: Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest 100, 259-263 (1997)
doi:10.1172/JCI119530
PMid:9458216
18. Ushiyama, T., Ueyama, H., Inoue, K., Nishioka, J., Ohkubo, I., Hukuda, S.: Estrogen receptor gene polymorphism and generalized osteoarthritis. J Rheumatol 25, 134-137 (1998)
PMid:10743824
19. Loughlin, J., Sinsheimer, J. S., Mustafa, Z., Carr A. J., Clipsham, K., Bloomfield, V. A., Chitnavis, J., Bailey, A., Sykes, B., Chapman, K.: Association analysis of the vitamin D receptor gene, the type I collagen gene COL1A1 and the estrogen receptor gene in idiopathic osteoarthritis. J Rheumatol 27, 779- 784 (2000)
PMid:10743824
20. Bergink, Arjan P., van Meurs, Joyce B., Loughlin, John, Arp, Pascal P., Fang, Yue, Hofman, Albert, van Leeuwen, Johannes P. T. M., van Duijn, Cornelia M., Uitterlinden, Andre G., Pols, Huibert A. P.: Estrogen receptor a gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women. Arthritis Rheum 48, 1913-1922 (2003)
doi:10.1002/art.11046
21. Jin, Sheng Yu, Hong, Seung Jae, Yang, Hyung In, Park, Sang do, Yoo, Myung Chul, Lee, Hee Jae, Hong, Mee Suk, Park, Hae Jeong, Yoon, Seo Hyun, Kim, Bum Shik, Yim, Sung Vin, Park, Hun Kuk, Chung, Joo Ho: Estrogen receptor-a gene haplotype is associated with primary knee osteoarthritis in Korean population. Arthritis Res Ther 6, R415-R421 (2004)
doi:10.1186/ar1207
22. Stern, Alan. G., de Carvalho, M. R. C., Buck, G. A., Adler, R. A., Rao, T. P. S., Disler, D., Moxley, G., I-NODAL Network: Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartilage 11, 394-402 (2003)
doi:10.1016/S1063-4584(03)00054-2
PMid:15190266
23. Smith, A. J. P., Keen, L. J., Billingham, M. J., Perry, M. J., Elson, C. J., Kirwan, J. R., Sims, J. E., Doherty, M., Spector, T. D., Bidwell, J. L.: Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 5, 451-460 (2004)
doi:10.1038/sj.gene.6364107
24. Meulenbelt, Ingrid, Seymour, Albert B., Nieuwland, Marja, Huizinga, Tom W. J., van Duijn, Cornelia M., Slagboom, P. Eline: Association of the interleukin-1 gene cluster with radiographic signs of osteoarthritis of the hip. Arthritis Rheum 50, 1179-1186 (2004)
doi:10.1002/art.20121
PMid:14745651
25. Forster, Tracy, Chapman, Kay, Loughlin, John: Common variants within the interleukin 4 receptor a gene (IL4R) are associated with susceptibility to osteoarthritis. Hum Genet 114, 391-395 (2004)
doi:10.1007/s00439-004-1083-0
PMid:10486325
26. Leppävuori, Jenni, Kujala, Urho, Kinnunen, Jaakko, Kaprio, Jaakko, Nissilä, Martti, Heliövaara, Markku, Klinger, Nina, Partanen, Jukka, Terwilliger, Joseph D., Peltonen, Leena: Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: evidence for a locus on 2q. Am J Hum Genet 65, 1060-1067 (1999)
doi:10.1086/302569
PMid:18471798 PMCid:2427208
27. Valdes, Ana M., Loughlin, John, Timms, Kirsten M., van Meurs, Joyce J. B., Southam, Lorraine, Wilson, Scott G., Doherty, Sally, Lories, Rik J., Luyten, Frank P., Gutin, Alexander, Abkevich, Victor, Ge, Dongliang, Hofman, Albert, Uitterlinden, Andre G., Hart, Deborah J., Zhang, Feng, Zhai, Guangju, Egli, Rainer J., Doherty, Michael, Lanchbury, Jerry, Spector, Tim D.: Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis. Am J Hum Genet 82, 1231-1240 (2008)
doi:10.1016/j.ajhg.2008.04.006
PMid:16642435
28. Mahr, Sandra, Burmester, Gerd-Rudiger, Hilke, Dietmar, Gobel, Udo, Grutzkau, Andreas, Haupl, Thomas, Hauschild, Matthias, Koczan, Dirk, Krenn, Veit, Neidel, Jasper, Perka, Carsten, Radbruch, Andreas, Thiesen, Hans-Jurgen, Muller, Brigitte: Cis- and trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet 78, 793-803 (2006)
doi:10.1086/503849
PMid:17304710
29. Loughlin, John, Meulenbelt, Ingrid, Min, Josine, Mustafa, Zehra, Sinsheimer, Janet S., Carr, Andrew, Slagboom, P. Eline: Genetic association analysis of RHOB and TXNDC3 in osteoarthritis. Am J Hum Genet 80, 383-386 (2007)
doi:10.1086/511443
PMid:11349230
30. Gedeon, A. K., Tiller, G. E., Le Merrer, M., Heuertz, S., Tranebjaerg, L., Chitayat, D., Robertson, S., Glass, I. A., Savarirayan, R., Cole, W. G., Rimoin, D. L., Kousseff, B. G., Ohashi, H., Zabel, B., Munnich, A., Gecz, J., Mulley, J. C.: The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet 68, 1386-1397 (2001)
doi:10.1086/320592
PMid:11326333
31. Tiller, George E., Hannig, Vickie L., Dozier, Damon, Carrel, Laura, Trevarthen, Karrie C., Wilcox, William R., Mundlos, Stefan, Haines, Jonathan L., Gedeon, Agi K., Gecz, Jozef: A recurrent RNA-splicing mutation in the SEDL gene causes X-Linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet 68, 1398-1407 (2001)
doi:10.1086/320594
PMid:17762607
32. Ikegawa,Shiro: New gene associations in osteoarthritis: What do they provide, and where are we going? Curr Opin Rheumatol 19, 429-434 (2007)
doi:10.1097/BOR.0b013e32825b079d
33. Forster, Tracy, Chapman, Kay, Marcelline, Lucy, Mustafa, Zehra, Southam, Lorraine, Loughlin, John: Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women. Arthritis Rheum 50, 98-102 (2004)
doi:10.1002/art.11427
PMid:12173034
34. Loughlin, John, Mustafa, Zehra, Dowling, Barbara, Southam, Lorraine, Marcelline, Lucy, Räinä, S Susanna, Ala-Kokko, Leena, Chapman, Kay: Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6. Eur J Hum Genet 10, 562-568 (2002)
doi:10.1038/sj.ejhg.5200848
PMid:7887424 PMCid:1801178
35. Baldwin, C. T., Farrer, L. A., Adair, R., Dharmavaram, R., Jimenez, S., Anderson, L.: Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q. Am J Hum Genet 56, 692-697 (1995)
PMid:10364529
36. Chapman, Kay, Mustafa, Zehra, Irven, Catherine, Carr, Andrew J., Clipsham, Kim, Smith, Anne, Chitnavis, Jai, Sinsheimer, Janet S., Bloomfield, Victoria A., McCartney, Mary, Cox, Olive, Cardon, Lon R., Sykes, Bryan, Loughlin, John: Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage. Am J Hum Genet 65, 167-174 (1999)
doi:10.1086/302465
37. Loughlin, John: Genetics of osteoarthritis and potential for drug development. Curr Opin Pharmacol 3, 295-299 (2003)
doi:10.1016/S1471-4892(03)00018-3
PMid:16773577
38. Mabuchi, Akihiko, Nakamura, Shigeru, Takatori, Yoshio, Ikegawa, Shiro: Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q. Am J Hum Genet 79, 163-168 (2006)
doi:10.1086/505088
PMid:20112360
39. Kerkhof, Hanneke J. M., Lories, Rik J., Meulenbelt, Ingrid, Jonsdottir, Ingileif, Valdes, Ana M., Arp, Pascal, Ingvarsson, Thorvaldur, Jhamai, Mila, Jonsson, Helgi, Stolk, Lisette, Thorleifsson, Gudmar, Zhai, Guangju, Zhang, Feng, Zhu, Yanyan, van der Breggen, Ruud, Carr, Andrew, Doherty, Michael, Doherty, Sally, Felson, David T., Gonzalez, Antonio, Halldorsson, Bjarni V., Hart, Deborah J., Hauksson, Valdimar B., Hofman, Albert, Ioannidis, John P. A., Kloppenburg, Margreet, Lane, Nancy E., Loughlin, John, Luyten, Frank P., Nevitt, Michael C., Parimi, Neeta, Pols, Huibert A. P., Rivadeneira, Fernando, Slagboom, Eline P., Styrkársdóttir, Unnur, Tsezou, Aspasia, van de Putte, Tom, Zmuda, Joseph, Spector, Tim D., Stefansson, Kari, Uitterlinden, André G., van Meurs, Joyce B. J.: A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum 62, 499-510 (2010)
PMid:7340843 PMCid:1163554
40. Videman, Tapio, Eronen, Iikka, Candolin, Tom: (3H)Proline-H-3 incorporation and hydroxyproline concentration in articular-cartilage during the development of osteoarthritis caused by immobilization. A study in vivo with rabbits. Biochem J 200, 435-440 (1981)
PMid:7340843 PMCid:1163554
41. Allen, Kyle D., Griffin, Timothy M., Rodriguiz, Ramona M., Wetsel, William C., Kraus, Virginia B., Huebner, Janet L., Boyd, Lawrence M., Setton, Lori A.: Mice deficient for type IX collagen have decreased physical function and increased pain sensitivity. Arthritis Rheum 60, 2684-2693 (2009)
doi:10.1002/art.24783
42. Hu, K., Xu, L., Cao, L., Flahiff, C. M., Brussiau, J., Ho, K., Setton, L. A., Youn, I., Guilak, F., Olsen, B. R., Li, Y. : Pathogenesis of osteoarthritis-like changes in the joints of mice deficient in type IX collagen. Arthritis Rheum 54, 2891-2900 (2006)
doi:10.1002/art.22040
43. Holmbeck, Kenn, Bianco, Paolo, Caterina, John, Yamada, Susan, Kromer, Mark, Kuznetsov, Sergei A., Mankani, Mahesh, Robey, Pamela Gehron, Poole, A. Robin, Pidoux, Isabelle, Ward, Jerrold M., Birkedal-Hansen, Henning: MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81-92 (1999)
PMid:15800624
44. Zemmyo, Michihisa, Meharra, E. John, Kühn, Klaus, Creighton-Achermann, Lilo, Lotz, Martin: Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthritis Rheum 48, 2873-2880 (2003)
doi:10.1002/art.11246
PMid:16896297
45. Glasson, Sonya S., Askew, Roger., Sheppard, Barbara, Carito, Brenda, Blanchet, Tracey, Ma, Hak-Ling, Flannery, Carl R., Peluso, Diane, Kanki, Kim, Yang, Zhiyong, Majumdar, Manas K., Morris, Elisabeth A.: Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nat 434, 644-648 (2005)
doi:10.1038/nature03369
PMid:17572112 PMCid:2062521
46. Ameye, Laurent G., Young, Marian F.: Animal models of osteoarthritis: lessons learned while seeking the "Holy Grail". Curr Opin Rheumatol 18, 537-547 (2006)
doi:10.1097/01.bor.0000240369.39713.af
PMid:15982479
47. Li, Yefu, Xu, Liangzhi, Olsen, Bjorn R.: Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthritis Cartilage 15, 1101-1105 (2007)
doi:10.1016/j.joca.2007.04.013
PMid:11978731
48. Young, Marian F.: Mouse models of osteoarthritis provide new research tools. Trends Pharmacol Sci 26, 333-335 (2005)
doi:10.1016/j.tips.2005.05.001
49. Ameye, Laurent, Aria, Dean, Jepsen, Karl, Oldberg, Ake, Xu, Tianshun, Young, Marian F.: Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. Faseb J 16, 673-680 (2002)
doi:10.1096/fj.01-0848com
PMid:7859284
50. Kannu, Peter, Bateman, John F., Belluoccio, Daniele, Fosang, Amanda J., Savarirayan, Ravi: Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60, 325-334 (2009)
doi:10.1002/art.24251
PMid:10520996
51. Chen, Jia Shing, Gupta, Tarun, Barasz, J. A., Kalajzic, Z., Yeh, W.-C., Drissi, Hicham, Hand, Alfred R., Wadhwa, Sunil: Analysis of microarchitectural changes in a mouse temporomandibular joint osteoarthritis model. Arch Oral Biol 54, 1091-1098 (2009)
doi:10.1016/j.archoralbio.2009.10.001
PMid:19896116
52. Lin, Alvin C.; Seeto, Brian L.; Bartoszko, Justyna M.; Khoury, Michael A.; Whetstone, Heather; Ho, Louisa; Hsu, Claire; Ali, S. Amanda; Alman, Benjamin A.: Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15, 1421-1426 (2009)
doi:10.1038/nm.2055
PMid:19915594
53. Châteauvert, J. M. D., Pritzker, K. P. H, Kessler, M. J., Grynpas, M. D.: Spontaneous osteoarthritis in rhesus macaques.II. Chemical and biochemical studies. J Rheumatol 16, 1098-1104 (1989)
54. Chateauvert, J. M. D., Grynpas, M. D., Kessler, M. J., Pritzker, K. P. H.: Spontaneous osteoarthritis in rhesus macaques. II. Characterization of disease and morphometric studies. J Rheumatol 17, 73-83 (1990)
PMid:2313678
55. Niebauer, Gert W., Wolf, Benjamin, Bashey, Reza I., Newton, Charles D.: Antibodies to canine collagen types I and II in dogs with spontaneous cruciate ligament rupture and osteoarthritis. Arthritis Rheum 30, 319-327 (1987)
doi:10.1002/art.1780300311
56. Liu, Wenhua, Burton-Wurster, Nancy, Glant, Tibor T., Tashman, Scott, Sumner, Dale R., Kamath, Rajesh V., Lust, George, Kimura, James H., Cs-Szabo, Gabriella: Spontaneous and experimental osteoarthritis in dog: similarities and differences in proteoglycan levels. J Orthop Res 21, 730-737 (2003)
doi:10.1016/S0736-0266(03)00002-0
57. Carney, S. L., Hicks, C. A., Tree, B., Broadmore, R. J.: An in vivo investigation of the effect of anthraquinones on the turnover of aggrecans in spontaneous osteoarthritis in the guinea pig. Inflamm Res 44, 182-186 (1995)
doi:10.1007/BF01782817
PMid:7670936
58. Kapadia, R. D., Badger, A. M., Levin, J. M., Swift, B., Bhattacharyya, A., Dodds, R. A., Coatney, R. W., Lark, M. W.: Meniscal ossification in spontaneous osteoarthritis in the guinea-pig. Osteoarthritis Cartilage 8, 374-377 (2000)
doi:10.1053/joca.1999.0312
PMid:10966844
59. Johnson, Kristen, Svensson, Camilla I., Etten, Deborah Van, Ghosh, Soumitra S., Murphy, Anne N., Powell, Henry C., Terkeltaub, Robert: Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthritis Rheum 50, 1216-1225 (2004)
doi:10.1002/art.20149
60. Anderson-MacKenzie, Janet M., Quasnichka, Helen L., Starr, Roger L., Lewis, E. Jonathan, Billingham, Michael E. J., Bailey, Allen J.: Fundamental subchondral bone changes in spontaneous knee osteoarthritis. Int J Biochem Cell Biol 37, 224-236 (2005)
PMid:15381164
61. Jimenez, Pablo A., Glasson, Sonya S., Trubetskoy, Olga V., Haimes, Howard B.: Spontaneous osteoarthritis in Dunkin Hartley guinea pigs: histologic, radiologic, and biochemical changes. Lab Anim Sci 47, 598-601 (1997)
PMid:9433695
62. De Bri, E., Lei, W., Svensson, O., Chowdhury, M., Moak, S. A., Greenwald, R. A.: Effect of an inhibitor of matrix metalloproteinases on spontaneous osteoarthritis in guinea pigs. Adv Dent Res 12, 82-85 (1998)
doi:10.1177/08959374980120012601
PMid:9972127
63. Han, B., Cole, A. A., Shen, Y., Brodie, T., Williams, James M.: Early alterations in the collagen meshwork and lesions in the ankles are associated with spontaneous osteoarthritis in guinea-pigs. Osteoarthritis Cartilage 10,778-784 (2002)
doi:10.1053/joca.2002.0822
PMid:12359163
64. Kraus, Virginia B., Huebner, Janet L., Stabler, Thomas, Flahiff, Charlene M., Setton, Lori A., Fink, Christian, Vilim, Vladimir, Clark, Amy G.: Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model. Arthritis Rheum 50, 1822-1831 (2004)
doi:10.1002/art.20291
65. Uchida, Kentaroo, Urabe, Ken, Naruse, Kouji, Ogawa, Zensuke, Mabuchi, Kiyoshi, Itoman, Moritoshi: Hyperlipidemia and hyperinsulinemia in the spontaneous osteoarthritis mouse model, STR/Ort. Exp Anim 58, 181-187 (2009)
doi:10.1538/expanim.58.181
PMid:19448342
66. Blaney Davidson, E. N., Vitters, E. L., van Beuningen, H. M., van de Loo, F. A. J., van den Berg, W. B., van der Kraan, P. M.: Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation. Arthritis Rheum 56, 4065-4073 (2007)
doi:10.1002/art.23034
67. Yamamoto, K.: Ultrastructural studies on the articular cartilage of spontaneous osteoarthritis in C 57 black mice. Nippon Seikeigeka Gakkai Zasshi 64, 648-665 (1990)
PMid:2230425
68. Stoop, Reinout, van der Kraan, Peter M., Buma, Pieter, Hollander, Anthony P., Billinghurst, R. Clark, Poole, A. Robin, van den Berg, Wim B.: Type II collagen degradation in spontaneous osteoarthritis in C57Bl/6 and BALB/c mice. Arthritis Rheum 42, 2381-2389 (1999)
doi:10.1002/1529-0131(199911)42:11<2381::AID-ANR17>3.0.CO;2-E
69. Anderson-MacKenzie, Janet M., Billingham, Michael E., Bailey, Allen J.: Collagen remodeling in the anterior cruciate ligament associated with developing spontaneous murine osteoarthritis. Biochem Biophys Res Commun 258, 763-767 (1999)
doi:10.1006/bbrc.1999.0713
PMid:10329460
70. Takahama, A.: Histological study on spontaneous osteoarthritis of the knee in C57 black mouse. Nippon Seikeigeka Gakkai Zasshi 64, 271-281 (1990)
PMid:2380590
71. Bennett, Granville A., Bauer, Walter, Maddock, Stephen J.: A study of the repair of articular cartilage and the reaction of normal joints of adult dogs to surgically created defects of articular cartilage, "joint mice"and patellar displacement. Am J Pathol 8, 499-524 (1932)
PMid:19970034 PMCid:2062622
72. Bruce, John, Walmsley, Robert: Excision of the patella - Some experimental and anatomical observations. J Bone Joint Surg 24, 311-325 (1942)
73. Rogart, J. N., Barrach, H. J., Chichester, C. O.: Articular collagen degradation in the Hulth-Telhag model of osteoarthritis. Osteoarthritis Cartilage 7, 539-547 (1999)
doi:10.1053/joca.1999.0258
PMid:10558852
74. Wu, Qi, Henry, James L.: Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis. Mol Pain 5, 57 (2009)
doi:10.1186/1744-8069-5-57
PMid:19785765 PMCid:2761878
75. Hayashi, Masaya, Muneta, Takeshi, Ju,Young-Jin, Mochizuki, Tomoyuki, Sekiya, Ichiro: Weekly intra-articular injections of bone morphogenetic-7 protein inhibits osteoarthritis progression. Arthritis Res Ther 10, R118 (2008)
doi:10.1186/ar2521
76. Proulx, Steven T., Kwok, Edmund, You, Zhigang, Papuga, M. Owen, Beck, Christopher A., Shealy, David J., Calvi, Laura M., Ritchlin, Christopher T. Awad, Hani A., Boyce, Brendan F., Xing, Lianping, Schwarz, Edward M.: Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging. Arthritis Rheum 58, 2019-2029 (2008)
doi:10.1002/art.23546
77. Johnson, Robert G., Poole, A Robin: Degenerative changes in dog articular cartilage induced by a unilateral tibial valgus osteotomy. Exp Pathol 33, 145-164 (1988)
PMid:3224676
78. Wei, L., Hjerpe, A., Brismar, B. H., Svensson, O.: Effect of load on articular cartilage matrix and the development of guinea-pig osteoarthritis. Osteoarthritis Cartilage 9, 447-453 (2001)
doi:10.1053/joca.2000.0411
PMid:11467893
79. Inerot, Sven, Heinegård, Dick, Olsson, Sten-Erik, Telhag, Hans, Audell, Lars: Proteoglycan alterations during developing experimental osteoarthritis in a novel hip joint model. J Orthop Res 9, 658-673 (1991)
doi:10.1002/jor.1100090506
PMid:1870030
80. Marijnissen, A. C. A., van Roermund, P. M., Verzijl, V, TeKoppele, J. M., Bijlsma, J. W. J., Lafeber, F. P. J. G.: Steady progression of osteoarthritic features in the canine groove model. Osteoarthritis Cartilage 10, 282-289 (2002)
doi:10.1053/joca.2001.0507
PMid:11950251
81. Marijnissen, A. C. A., van Roermund, P. M., TeKoppele, J. M., Bijlsma, J. W. J., Lafeber, F. P. J. G.: The canine "groove" model, compared with the ACLT model of osteoarthritis. Osteoarthritis Cartilage 10, 145-155 (2002)
doi:10.1053/joca.2001.0491
PMid:11869074
82. Høegh-Andersen, Pernille, Tankó, László B, Andersen, Thomas L., Lundberg, Carina V., Mo, John A., Heegaard, Anne-Marie, Delaissé, Jean-Marie, Christgau, Stephan: Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther 6, R169-R180 (2004)
doi:10.1186/ar1152
83. Arsever, Christiane L., Bole, Giles G.: Experimental osteoarthritis induced by selective myectomy and tendotomy. Arthritis Rheum 29, 251-261 (1986)
doi:10.1002/art.1780290214
84. Layton, Mark W., Goldstein, Steven A., Goulet, Robert W., Feldkamp, Lee A., Kubinski, David J., Bole, Giles G.: Examination of subchondral bone architecture in experimental osteoarthritis by microscopic computed axial tomography. Arthritis Rheum 31, 1400-1405 (1988)
doi:10.1002/art.1780311109
85. Videman, Tapio, Eronen, Ilkka, Friman, Claes, Langenskiöld, Anders: Glycosaminoglycan metabolism of the medial meniscus, the medial collateral ligament and the hip joint capsule in experimental osteoarthritis caused by immobilization of the rabbit knee. Acta Orthop Scand 50, 465-470 (1979)
doi:10.3109/17453677908989791
86. Konttinen, Y. T., Michelsson, J. E., Tolvanen, E., Bergroth, V.: Primary inflammatory reaction in synovial fluid and tissue in rabbit immobilization osteoarthritis. Clin Orthop Relat Res 260, 280-286 (1990)
PMid:2225634
87. Konttinen, Y. T., Michelsson, J. E., Grönblad, M., Jaakkola, L., Honkanen, V.: Plasma hyaluronan levels in rabbit immobilization osteoarthritis: effect of remobilization. Scand J Rheumatol 20, 392-396 (1991)
doi:10.3109/03009749109096817
PMid:1771397
88. Reimann, Inge: Experimental osteoarthritis of the knee in rabbits induced by alteration of the load-bearing. Acta Orthop Scand 44, 496-504 (1973)
doi:10.3109/17453677308989085
89. Pritzker, Kenneth P. H.: Animal-models for osteoarthritis: processes, probelms and prospects. Ann Rheum Dis 53, 406-420 (1994)
doi:10.1136/ard.53.6.406
PMid:8037500 PMCid:1005358
90. Huser, Camille A. M., Davies, M. Elisabeth: Validation of an in vitro single-impact load model of the initiation of osteoarthritis-like changes in articular cartilage. J Orthop Res 24, 725-732 (2006)
doi:10.1002/jor.20111
PMid:16514652
91. Borrelli, Joseph Jr., Silva, Matthew J., Zaegel, Melissa A., Franz, Carl, Sandell, Linda J.: Single high-energy impact load causes posttraumatic OA in young rabbits via a decrease in cellular metabolism. J Orthop Res 27, 347-352 (2009)
doi:10.1002/jor.20760
PMid:18924142
92. Simon, W. H., Richardson, S., Herman, W., Parsons, J. R., Lane, J.: Long-term effects of chondrocyte death on rabbit articular cartilage in vivo. J Bone Joint Surg Am 58, 517-526 (1976)
PMid:57962
93. Kim, H. K, Moran, M. E, Salter, R. W.: The potential for regeneration of articular cartilage in defects created by chondral shaving and subchondral abrasion. J Bone Joint Surg Am 73A, 1301-1315 (1991)
94. Altman, Roy D., Kates, Jonathan, Chun, Lawrence, E., Dean, D. David, Eyre, David: Preliminary observations of chondral abrasion in a canine model. Ann Rheum Dis 51, 1056-1062 (1992)
doi:10.1136/ard.51.9.1056
PMid:1417137 PMCid:1004837
95. Weinberger, A., Schumacher, H. R.: Experimental joint trauma: synovial response to blunt trauma and inflammatory reaction to intraarticular injection of fat. J Rheumatol 8, 380-389 (1981)
PMid:7288755
96. Hjertquist, Sven Olof, Lemperg, Rudolf: Histological, autoradiographic and microchemical studies of spontaneously healing osteochondral articular defects in adult rabbits. Calcif Tissue Res 8, 54-72 (1971)
doi:10.1007/BF02010122
PMid:4257514
97. Van Sickle, D. C.: Experimental models of osteoarthritis. In: Comparative pathobiologv of major age-related diseases: current status and research frontiers. Eds: Scarpelli D G, Migaki G. Alan R Liss, NY (1984)
98. Piecha, Dorothea, Weik, Jürgen, Kheil, Heike, Becher, Gabriele, Timmermann, Andreas, Jaworski, Andreas, Burger, Maren, Hofmann, Michael W.: Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants. Inflamm Res 59, 379-389 (2010)
doi:10.1007/s00011-009-0112-9
PMid:19902332
99. Lorenz, Helga, Richter, Wiltrud: Osteoarthritis: Cellular and molecular changes in degenerating cartilage. Prog Histochem Cyto 40, 135-163 (2006)
doi:10.1016/j.proghi.2006.02.003
PMid:16759941
100. Wollheim, Frank A.: Serum markers of articular cartilage damage and repair. Rheum Dis Clin North Am 25, 417-432 (1999)
doi:10.1016/S0889-857X(05)70076-4
101. Peach, Chris A., Carr, Andrew J., Loughlin, John: Recent advances in the genetic investigation of osteoarthritis. Trends Mol Med 11, 186-191 (2005)
doi:10.1016/j.molmed.2005.02.005
PMid:15823757
102. Tew, Simon, Redman, Samantha, Kwan, Alvin, Walker, Elizabeth, Khan, Ilyas, Dowthwaite, Gary, Thomson, Brian, Archer, Charles W.: Differences in repair responses between immature and mature cartilage. Clin Orthop Relat Res 391, S142-S152 (2001)
doi:10.1097/00003086-200110001-00014
PMid:11603699
103. Homandberg, Gene A.: Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Frontiers in Bioscience 4, D713-D730 (1999)
doi:10.2741/Homandberg
PMid:10525477
104. Tesche, F., Miosge, N.: New aspects of the pathogenesis of osteoarthritis: the role of fibroblast-like chondrocytes in late stages of the disease. Histol Histopathol 20, 329-337 (2005)
PMid:15578449
105. Martinek, V.: Anatomy and pathophysiology of articular cartilage. Dtsch Z Sportmed 54, 166-170 (2003)
106. Nakashima, Kazuhisa, de Crombrugghe, Benoit: Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet 19, 458-466 (2003)
doi:10.1016/S0168-9525(03)00176-8
107. Jiao, Kai; Niu, Li Na; Wang, Mei Qing; Dai, Juan; Yu, Shi Bin; Liu, Xiao Dong; Wang, Jun: Subchondral bone loss following orthodontically induced cartilage degradation in the mandibular condyles of rats. Bone (2010)
108. Botter, S.M.; van Osch, G. J. V. M.; Waarsing, J. H.; van der Linden, J. C.; Verhaar, J. A.; Pols, H. A.; van Leeuwen, J. P. T. M.; Weinans, H.: Cartilage damage pattern in relation to subchondral plate thickness in a collagenase-induced model of osteoarthritis. Osteoarthritis Cartilage 16, 506-514 (2008)
doi:10.1016/j.joca.2007.08.005
PMid:17900935
109. Dewire, P., Einhorn, T. A.: The joint as an organ. In: Osteoarthritis. Eds: R. W. Moskowitz, D. S. Howell, R. D. Altman, J. A. Buckwalter, V. M. Goldberg Diagnosis and Medical/Surgical Management, W.B. Saunders Company, Philadelphia (2001)
110. Sellam, Jeremie; Berenbaum, Francis: The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 6, 625-635 (2010)
doi:10.1038/nrrheum.2010.159
PMid:20924410
111. Ogawa, Kenji; Mawatari, Masaaki; Komine, Mitsunori; Shigematsu, Masamori; Kitajima, Masaru; Kukita, Akiko; Hotokebuchi, Takao: Mature and activated osteoclasts exist in the synovium of rapidly destructive coxarthrosis. J Bone Miner Metab 25, 354-360 (2007)
doi:10.1007/s00774-007-0761-0
PMid:17968487
112. Bonnet, C. S., Walsh, D. A.: Osteoarthritis, angiogenesis and inflammation. Rheumatology 44, 7-16 (2005)
doi:10.1093/rheumatology/keh344
PMid:15292527
113. Clark, Ian M., Parker, Andrew E.: Metalloproteinases: their role in arthritis and potential as therapeutic targets. Expert Opin Ther Tar 7, 19-34 (2003)
doi:10.1517/14728222.7.1.19
PMid:12556200
114. Yagi, Rieko, McBurney, Denise, Laverty, David, Weiner, Scott, Horton, Walter E.: Intrajoint comparisons of gene expression patterns in human osteoarthritis suggest a change in chondrocyte phenotype. J Orthop Res 23, 1128-1138 (2005)
doi:10.1016/j.orthres.2004.12.016
PMid:15936918
115. Le Graverand, Marie-Pierre Hellio, Eggerer, Jonna, Vignon, Eric, Otterness, Ivan G., Barclay, Leona, Hart, David A.: Assessment of specific mRNA levels in cartilage regions in a lapine model of osteoarthritis. J Orthop Res 20, 535-544 (2002)
doi:10.1016/S0736-0266(01)00126-7
116. Salminen, H. J., Säämänen, A-M. K., Vankemmelbeke, M. N., Auho, P. K., Perälä, M. P., Vuorio, E. I.: Differential expression patterns of matrix metalloproteinases and their inhibitors during development of osteoarthritis in a transgenic mouse model. Ann Rheum Dis 61, 591-597 (2002)
doi:10.1136/ard.61.7.591
PMid:12079898 PMCid:1754156
117. Martel-Pelletier, Johanne: Pathophysiology of osteoarthritis. Osteoarthritis Cartilage 6, 374-376 (1998)
doi:10.1053/joca.1998.0140
PMid:10343769
118. Wang, Pu, Zhu, Fei, Lee, Norman H., Konstantopoulos, Konstantinos: Shear-induced interleukin-6 synthesis in chondrocytes: the roles of E prostanoid (EP)2 and EP3 in cAMP/protein kinase A- and PI3-K/Akt-dependent NF-{kappa}B activation. J Biol Chem 285, 24793-24804 (2010)
doi: 10.1074/jbc.M110.110320
119. Santos, M. L. A. S., Gomes, W. F., Pereira, D. S., Oliveira, D. M. G., Dias, J. M. D., Ferrioli, E., Pereira, L. S. M. Muscle strength, muscle balance, physical function and plasma interleukin-6 (IL-6) levels in elderly women with knee osteoarthritis (OA). Arch Gerontol Geriatr (2010)
doi:10.1016/j.archger.2010.05.009
PMid:20627334
120. Kirkham, Bruce: Interleukin-1, immune activation pathways, and different mechanisms in osteoarthritis and rheumatoid arthritis. Ann Rheum Dis 50, 395-400 (1991)
doi:10.1136/ard.50.6.395
PMid:2059083 PMCid:1004446
121. Ning, Liang, Ishijima, Muneaki, Kaneko, Haruka, Kurihara, Hidetake, Arikawa-Hirasawa, Eri, Kubota, Mitsuaki, Liu, Lizu, Xu, Zhuo, Futami, Ippei, Yusup, Anwarjan, Miyahara, Katsumi, Xu, Shouyu, Kaneko, Kazuo, Kurosawa, Hisashi: Correlations between both the expression levels of inflammatory mediators and growth factor in medial perimeniscal synovial tissue and the severity of medial knee osteoarthritis. Int Orthop (2010)
doi:10.1007/s00264-010-1045-1
PMid:20517696
122. Schubert, T., Denk, A., Maegdefrau, U., Kaufmann, S., Bastone, P., Lowin, T., Schedel, J., Bosserhoff, A. K.: Role of the netrin system of repellent factors on synovial fibroblasts in rheumatoid arthritis and osteoarthritis. Int J Immunopathol Pharmacol 22, 715-722 (2009)
PMid:19822088
123. Logar, Darja Bitenc; Komadina, Radko; Prezelj, Janez; Ostanek, Barbara; Trost, Zoran; Marc, Janja: Expression of bone resorption genes in osteoarthritis and in osteoporosis. J Bone Miner Metab 25, 219-225 (2007)
doi:10.1007/s00774-007-0753-0
PMid:17593491
124. Andersson, Martin K.; Lundberg, Pernilla; Ohlin, Acke; Perry, Mark J.; Lie, Anita; Stark, Andre; Lerner, Ulf H.: Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients. Arthritis Res Ther 9, R18 (2007)
doi:10.1186/ar2127
125. Sandell, Linda J., Aigner, Thomas: Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res 3, 107-113 (2001)
doi:10.1186/ar148
PMid:11178118 PMCid:128887
doi:10.1186/ar276
126. Lee, Yu Tsang, Shao, Hung Jen, Wang, Jyh Horng, Liu, Haw Chang, Hou, Sheng Mou, Young, Tai Horng: Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro. J Orthop Res 28, 492-496 (2010)
PMid:19890996
127. Tat, Steeve Kwan, Pelletier, Jean-Pierre, Velasco, Carmen Ruiz, Padrines, Marc, Martel-Pelletier, Johanne: New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target? Keio J Med 58, 29-40 (2009)
doi:10.2302/kjm.58.29
PMid:19398882
128. Sutton, Saski, Clutterbuck, Abigail, Harris, Pat, Gent, Thom, Freeman, Sarah, Foster, Neil, Barrett-Jolley, Richard, Mobasheri, Ali: The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet J 179, 10-24 (2009)
doi:10.1016/j.tvjl.2007.08.013
PMid:17911037
129. Martin, James A., Buckwalter, Joseph A.: Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa Orthop J 21, 1-7 (2001)
PMid:11813939 PMCid:1888191
130. Yao, Zhenqiang; Xing, Lianping; Boyce, Brendan F.: NF-kappaB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J Clin Invest 119, 3024-3034 (2009)
doi:10.1172/JCI38716
PMid:19770515 PMCid:2752069
131. Fukuda, Kanji: Progress of Research for Osteoarthritis. Involvement of reactive oxygen species in the pathogenesis of osteoarthritis. Clin Calcium 19, 1602-1606 (2009)
PMid:19880992
132. Scott, Jenny L., Gabrielides, Christos, Davidson, Rose K., Swingler, Tracey E., Clark, Ian M., Wallis, Gillian A., Boot-Handford, Raymond P., Kirkwood, Tom B. L., Talyor, Robert W., Young, David A.: Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Ann Rheum Dis 69, 1502-1510 (2010)
doi:10.1136/ard.2009.119966
PMid:20511611
133. Milner, Jennifer M., Patel, Amit, Davidson, Rose K., Swingler, Tracey E., Desilets, Antoine, Young, David A., Kelso, Elizabeth B., Donell, Simon T., Cawston, Tim E., Clark, Ian M., Ferrell, William R., Plevin, Robin, Lockhart, John C., Leduc, Richard, Rowan, Andrew D.: Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum 62, 1955-1966 (2010)
PMid:20506309
134. Caramés, Beatriz, Taniguchi, Noboru, Otsuki, Shubei, Blanco, Francisco J., Lotz, Martin: Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 62, 791-801 (2010)
doi:10.1002/art.27305
135. Goldring, Mary B.: The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43, 1916-1926 (2000)
doi:10.1002/1529-0131(200009)43:9<1916::AID-ANR2>3.0.CO;2-I
136. Brooks, Peter: Inflammation as an important feature of osteoarthritis. Bull World Health Organ 81, 689-690 (2003)
PMid:14710513 PMCid:2572543
137. Corr, Maripat: Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis. Nat Clin Pract Rheum 4, 550-556 (2008)
doi:10.1038/ncprheum0904
PMid:18820702
138. Nakase, T., Miyaji, T., Tomita, T., Kaneko, M., Kuriyama, K., Myoui, A., Sugamoto, K., Ochi, T., Yoshikawa, H.:Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte. Osteoarthritis Cartilage 11, 278-284 (2003)
doi:10.1016/S1063-4584(03)00004-9
139. Dell'Accio, Francesco, De Bari, Cosimo, El Tawil, Noha M. F., Barone, Francesca, Mitsiadis, Thimios A., O'Dowd, John, Pitzalis, Costantino: Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Res Ther 8, R139 (2006)
doi:10.1186/ar2029
140. Zuscik, Michael J., Baden, Jonathan F., Wu, Qiuqian, Sheu, Tzong J., Schwarz, Edward M., Drissi, Hicham, O'Keefe, Regis J., Puzas, J. Edward, Rosier, Randy N.: 5-azacytidine alters TGF-beta and BMP signaling and induces maturation in articular chondrocytes. J Cell Biochem 92, 316-331 (2004)
doi:10.1002/jcb.20050
PMid:15108358
141. Arai, Maya, Anderson, Dina, Kurdi, Yahya, Annis-Freeman, Bethany, Shields, Kathleen, Collins-Racie, Lisa A., Corcoran, Christopher, DiBlasio-Smith, Elizabeth, Pittman, Debra D., Dorner, Andrew J., Morris, Elisabeth, LaVallie, Edward R.: Effect of adenovirus-mediated overexpression of bovine ADAMTS-4 and human ADAMTS-5 in primary bovine articular chondrocyte pellet culture system. Osteoarthritis Cartilage 12, 599-613 (2004)
doi:10.1016/j.joca.2004.05.001
PMid:15262240
142. Rountree, Ryan B., Schoor, Michael, Chen, Hao, Marks, Melissa E., Harley, Vincent, Mishina, Yuji, Kingsley, David M.: BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLos Biol 2, e355 (2004)
doi:10.1371/journal.pbio.0020355
PMid:15492776 PMCid:523229
143. Ikegawa, Shiro: Expression, regulation and function of asporin, a susceptibility gene in common bone and joint diseases. Curr Med Chem 15, 724-728 (2008)
doi:10.2174/092986708783885237
PMid:18336287
144. Haag, Jochen, Aigner, Thomas: Identification of calponin 3 as a novel Smad-binding modulator of BMP signaling expressed in cartilage. Exp Cell Res 313, 3386-3394 (2007)
doi:10.1016/j.yexcr.2007.08.003
PMid:17825283
145. Reddi, A. Hari: Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN. Arthritis Res 3, 1-5 (2001)
doi:10.1186/ar133
PMid:11178121 PMCid:128877
146. Tardif, G., Pelletier, J-P., Hum, D., Boileau, C., Duval, N., Martel-Pelletier, J.: Differential regulation of the bone morphogenic protein antagonist chordin in human normal and osteoarthritic chondrocytes. Ann Rheum Dis 65, 261-264 (2006)
doi:10.1136/ard.2005.037523
PMid:16410531 PMCid:1798027
147. Wang, Hao, Zhang, Jishuai, Sun, Qiang, Yang, Xiao: Altered gene expression in articular chondrocytes of Smad3(ex8/ex8) mice, revealed by gene profiling using microarrays. J Genet Genomics 34, 698-708 (2007)
doi:10.1016/S1673-8527(07)60079-4
148. Li, Tian Fang, Darowish, Michael, Zuscik, Michael J., Chen, Di, Schwarz, Edward M., Rosier, Randy N., Drissi, Hicham, O'Keefe, Regis J.: Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Mine Res 21, 4-16 (2006)
doi:10.1359/JBMR.050911
PMid:16355269 PMCid:2649698
149. Goldring, M. B., Otero, M., Tsuchimochi, K., Ijiri, K., Li, Y.: Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis 67, 75-82 (2008)
doi:10.1136/ard.2008.098764
PMid:19022820
150. Fukui, Naoshi, Zhu, Yong, Maloney, William J., Clohisy, John, Sandell, Linda J.: Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg Am 85A, 59-66 (2003)
151. Shi, J., Schmitt-Talbot, E., DiMattia, D. A., Dullea, R. G.: The differential effects of IL-1 and TNF-alpha on proinflammatory cytokine and matrix metalloproteinase expression in human chondrosarcoma cells. Inflamm Res 53, 377-389 (2004)
doi:10.1007/s00011-004-1271-3
PMid:15316669
152. Lee, Sang Yang, Nakagawa, Toshiyuki, Reddi, A. Hari: Induction of chondrogenesis and expression of superficial zone protein (SZP)/lubricin by mesenchymal progenitors in the infrapatellar fat pad of the knee joint treated with TGF-beta1 and BMP-7. Biochem Biophys Res Commun 376, 148-153 (2008)
doi:10.1016/j.bbrc.2008.08.138
PMid:18774772
153. Li, Kelvin W., Siraj, Sebrin A., Cheng, Erika W., Awada, Mohamad, Hellerstein, Marc K., Turner, Scott M.: A stable isotope method for the simultaneous measurement of matrix synthesis and cell proliferation in articular cartilage in vivo. Osteoarthritis Cartilage 17, 923-932 (2009)
doi:10.1016/j.joca.2009.01.006
PMid:19230856 PMCid:2763636
154. Hoberg, M., Uzunmehmetoglu, G., Sabic, L., Reese, S., Aicher, W. K., Rudert, M.: Characterisation of human meniscus cells. Z Orthop Grenzgeb 144, 172-178(2006)
doi:10.1055/s-2006-933364
PMid:16625447
155. Couchourel, Denis, Aubry, Isabelle, Delalandre, Aline, Lavigne, Martin, Martel-Pelletier, Johanne, Pelletier, Jean-Pierre, Lajeunesse, Daniel: Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production. Arthritis Rheum 60, 1438-1450 (2009)
doi:10.1002/art.24489
156. Shibakawa, A., Yudoh, K., Masuko-Hongo, K., Kato, T., Nishioka, K., Nakamura, H.: The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow. Osteoarthritis Cartilage 13, 679-687 (2005)
doi:10.1016/j.joca.2005.04.010
PMid:15961327
157. Blom, Arjen B., van Lent, Peter L. E. M., Holthuysen, Astrid E. M., van der Kraan, Peter M., Roth, Johannes, van Rooijen, Nico, van den Berg, Wim B.: Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 12, 627-635 (2004)
doi:10.1016/j.joca.2004.03.003
PMid:15262242
158. Scharstuhl, Alwin, Vitters, Elly L., van der Kraan, Peter M., van den Berg, Wim B.: Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum 48, 3442-3451 (2003)
doi:10.1002/art.11328
159. Wu, M. J., Gu, Z. Y., Sun, W.: Effects of hydrostatic pressure on cytoskeleton and BMP-2, TGF-beta, SOX-9 production in rat temporomandibular synovial fibroblasts. Osteoarthritis Cartilage 16, 41-47 (2008)
doi:10.1016/j.joca.2007.05.024
PMid:17631391
160. Lee, Sahnghoon, Kim, Ji Hyun, Jo, Chris Hyunchul, Seong, Sang Cheol, Lee, Jae Chul, Lee, Myung Chul: Effect of serum and growth factors on chondrogenic differentiation of synovium-derived stromal cells. Tissue Eng Part A 15, 3401-3415 (2009)
doi:10.1089/ten.tea.2008.0466
PMid:19402787
161. Bramlage, Carsten P., Häupl, Thomas, Kaps, Christian, Ungethüm, Ute, Krenn, Veit, Pruss, Axel, Ungethüm, Gerhard A., Strutz, Frank, Burmester, Gerd-R.: Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 8, R58 (2006)
doi:10.1186/ar1923
162. Honsawek, Sittisak, Chayanupatkul, Maneerat, Tanavalee, Aree, Sakdinakiattikoon, Manoon, Deepaisarnsakul, Benjamad, Yuktanandana, Pongsak, Ngarmukos, Srihatach: Relationship of plasma and synovial fluid BMP-7 with disease severity in knee osteoarthritis patients: a pilot study. Int orthop 33, 1171-1175 (2009)
doi:10.1007/s00264-009-0751-z
PMid:19301001
163. Blaney Davidson, E. N., Vitters, E. L., van der Kraan, P. M., van den Berg, W. B.: Expression of transforming growth factor-beta (TGFbeta) and the TGFbeta signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis 65, 1414-1421 (2006)
doi:10.1136/ard.2005.045971
PMid:16439443 PMCid:1798346
164. Blaney Davidson, Esmeralda N., Vitters, Elly L., van Lent, Peter L. E. M., van de Loo, Fons A. J., van den Berg, Wim B., van der Kraan, Peter M.: Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling. Arthritis Res Ther 9, R102 (2007)
doi:10.1186/ar2126
165. Frenkel, Sally R., Saadeh, Pierre B., Mehrara, Babak J., Chin, Gyu S. M. D., Steinbrech, Douglas S., Brent, Burt, Gittes, George K., Longker, Michael T.: Transforming growth factor beta superfamily members: role in cartilage modeling. Plast Reconstr Surg 105, 980-990 (2000)
doi:10.1097/00006534-200003000-00022
166. Nixon, Alan J., Goodrich, Laurie R., Scimeca, Michael S., Witte, Thomas H., Schnabel, Lauren V., Watts, Ashlee E., Robbinsc, Paul D.: Gene therapy in musculoskeletal repair. Ann N Y Acad Sci 1117, 310-327 (2007)
doi:10.1196/annals.1402.065
PMid:18056051
167. Matsumoto, Tomoyuki, Cooper, Gregory M., Gharaibeh, Burhan, Meszaros, Laura B., Li, Guangheng, Usas, Arvydas, Fu, Freddie H., Huard, Johnny: Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arthritis Rheum 60, 1390-1405 (2009)
doi:10.1002/art.24443
168. Sekiya, Ichiro, Tang, Tao, Hayashi, Masaya, Morito, Toshiyuki, Ju, Young Jin, Mochizuki, Tomoyuki, Muneta, Takeshi: Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats. J Orthop Res 27, 1088-1092 (2009)
doi:10.1002/jor.20840
PMid:19170094
169. Hurtig, Mark, Chubinskaya, Susan, Dickey, Jim, Rueger, David: BMP-7 protects against progression of cartilage degeneration after impact injury. J Orthop Res 27, 602-611 (2009)
doi:10.1002/jor.20787
PMid:18985691
170. Chubinskaya, Susan, Hurtig, Mark, Rueger, David C.: OP-1/BMP-7 in cartilage repair. Int orthop 31, 773-781 (2007)
doi:10.1007/s00264-007-0423-9
PMid:17687553 PMCid:2266666
171. Stove, J., Schneider-Wald B., Scharf, H.-P., Schwarz, M. L.: Bone morphogenetic protein 7 (bmp-7) stimulates proteoglycan synthesis in human osteoarthritic chondrocytes in vitro. Biomed Pharmacother 60, 639-643 (2006)
doi:10.1016/j.biopha.2006.09.001
172. Canfield, A. E., Hadfield, K. D., Rock, C. F., Wylie, E. C., Wilkinson, F. L.: HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans 35, 669-671 (2007)
doi:10.1042/BST0350669
PMid:17635117
173. Pufe, Thomas, Petersen, Wolf, Fändrich, Fred, Varoga, Deike, Wruck, Christoph J., Mentlein, Rolf, Helfenstein, Andreas, Hoseas, Daniela, Dressel, Stefanie, Tillmann, Bernhard, Ruhnke, Maren: Programmable cells of monocytic origin (PCMO): a source of peripheral blood stem cells that generate collagen type II-producing chondrocytes. J Orthop Res 26, 304-313 (2008)
doi:10.1002/jor.20516
PMid:17963214
174. Yamada, Satoru, Tomoeda, Miki, Ozawa, Yasuhiro, Yoneda, Shinya, Terashima, Yoshimitsu, Ikezawa, Kazuhiko, Ikegawa, Shiro, Saito, Masahiro, Toyosawa, Satoru, Murakami, Shinya: PLAP-1/asporin, a novel negative regulator of periodontal ligament mineralization. J Biol Chem 282, 23070-23080 (2007)
doi:10.1074/jbc.M611181200
PMid:17522060
175. Hopwood, Blair, Tsykin, Anna, Findlay, David M., Fazzalari, Nicola L.: Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-beta/bone morphogenic protein signalling. Arthritis Res Ther 9, R100 (2007)
doi:10.1186/ar2301
176. Alvarez-Soria, M. A., Largo, R., Santillana, J., Sanchez-Pernaute, O., Calvo, E., Hernandez, M., Egido, J., Herrero-Beaumont, G.: Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac. Ann Rheum Dis 65, 998-1005 (2006)
doi:10.1136/ard.2005.046920
PMid:16476713 PMCid:1798252
177. Berenbaum, Francis: New horizons and perspectives in the treatment of osteoarthritis. Arthritis Res Ther 10, S1 (2008)
doi:10.1186/ar2462
178. Saggioro, A., Alvisi, V., Blasi, A., Dobrilla, G., Fioravanti, A., Marcolengo, R.: Misoprostol prevents NSAID-induced gastroduodenal lesions in patients with osteoarthritis and rheumatoid arthritis. Ital J Gastroenterol 23, 119-123 (1991)
PMid:1742504
179. Caldwell, J. R., Roth, S. H., Bohan, A., Brandon, M. L., Carstens, S. A., Chubick, A., Ferraro, L., Finch, W. R., Fleischmann, R. M., Gordon, R. D., Greco, T., Harris, E. R., Hirschberg, J. M., Kohn, N. N., Maurer, K. H., Miller, J. L., Owens, D., Rutstein, J. E., Samuels, B. S., Utsinger, P. D., Whelton, J. C.: A double blind study comparing the efficacy and safety of enteric coated naproxen to naproxen in the management of NSAID intolerant patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 21, 689-695 (1994)
PMid:8035394
180. de Bock, C. H., Hermans, J., van Marwijk, H. W. J., Kaptein, A. A., Mulder, I. D.: Health-related quality of life assessments in osteoarthritis during NSAID treatment. Pharm World Sci 18, 130-136 (1996)
doi:10.1007/BF00717728
PMid:8873228
181. Bradley, John. D., Brandt, Kenneth D., Katz, Barry P., Kalasinski, Lorrie A., Ryan, Sarah I.: Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 325, 87-91 (1991)
PMid:2052056
182. Williams, H. James, Ward, John R., Egger, Marlene J., Neuner, Rosemarie, Brooks, Raye H., Clegg, Daniel O., Field, Elizabeth H., Skosey, John L., Alarcón, Graciela S., Willkens, Robert F., Paulus, Harold E., Russell, I. Jon, Sharp, John T.: Comparison of naproxen and acetaminophen in a 2-year study of treatment of osteoarthritis of the knee.Arthritis Rheum 36, 1196-1206 (1993)
183. Towheed, Tanveer, Maxwell, Lara, Judd, Maria Catton, Michelle, Hochberg, Marc C., Wells, George A.: Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 25, CD004257 (2006)
184. Zhang, W., Jones, A., Doherty, M.: Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? a meta-analysis of randomised controlled trials. .Ann Rheum Dis 63, 901-907 (2004)
doi:10.1136/ard.2003.018531
PMid:15020311 PMCid:1755098
185. Schiødt, Frank V., Rochling, Fedja A., Casey, Donna L., Lee, William M.: Acetaminophen toxicity in an urban county hospital. N Engl J Med 337, 1112-1117 (1997)
PMid:9329933
186. Whitcomb, David C., Block, Geoffrey D.: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 272, 1845-1850 (1994)
PMid:8361867
187. Seifert, C. F., Lucas, D. S., Vondracek, T. G., Kastens, D. J., Mccarty, D. L., Bui, B.: Patterns of acetaminophen use in alcoholic patients. Pharmacotherapy 13, 391-395 (1993)
PMid:7990219
188. Henrich, William L., Agodoa, Lawrence E., Barrett, Brendan, Bennett, William M., Blantz, Roland C., Buckalew, Vardaman M., D'Agati, Vivette D., DeBroe, Marc E., Duggin, Geoffrey G., Eknoyan, Garabed, Elseviers, Monique M., Gomez, R. Ariel, Matzke, Gary R., Porter, George A., Sabatini, Sandra, Stoff, Jeffrey S., Striker, Gary E., Winchester, James F.: Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis 27, 162-165 (1996)
doi:10.1016/S0272-6386(96)90046-3
189. The management of chronic pain in older persons: AGS panel on chronic pain in older persons. American Geriatrics Society. Geriatrics 53, S8-S24 (1998)
190. Ezzo, Jeanette, Hadhazy, Victoria, Birch, Stephen, Lao, Lixing, Kaplan, Gary, Hochberg, Marc, Berman, Brian: Acupuncture for osteoarthritis of the knee: A systematic review. Arthritis Rheum 44, 819-825 (2001)
doi:10.1002/1529-0131(200104)44:4<819::AID-ANR138>3.3.CO;2-G
191. Lansdown, Harriet, Howard, Katie, Brealey, Stephen, MacPherson, Hugh: Acupuncture for pain and osteoarthritis of the knee: a pilot study for an open parallel-arm randomised controlled trial. BMC Musculoskelet Disord 10, 130 (2009)
doi:10.1186/1471-2474-10-130
PMid:19852841 PMCid:2775018
192. Park, Sung Hoon, Kim, Seong Kyu, Shin, Im Hee, Kim, Hyung Gun, Choe, Jung Yoon: Effects of aif on knee osteoarthritis patients: double-blind, randomized placebo-controlled study. Korean J Physiol Pharmacol 13, 33-37 (2009)
doi:10.4196/kjpp.2009.13.1.33
PMid:19885024 PMCid:2766718
193. Cameron, Melainie, Gagnier, Joel J., Little, Christine V., Parsons, Tessa J., Bluemle, Anette, Chrubasik, Sigrun: Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part 1: Osteoarthritis. Phytother Res 23, 497-515 (2009)
194. Myers, Stephen P., O' Connor, Joan, Fitton, J. Helen, Brooks, Lyndon, Rolfe, Margaret, Connellan, Paul, Wohlmuth, Hans, Cheras, Phil A., Morris, Carol: A combined phase I and II open label study on the effects of a seaweed extract nutrient complex on osteoarthritis. Biologics 4, 33-44 (2010)
PMid:20376172 PMCid:2846142
195. Kim, Joon Ki, Kim, Tae Hoon, Park, Sang Won, Kim, Hyo Yeon, Kim, Sang hoon, Lee, Sung youl, Lee, Sun Mee: Protective effects of human placenta extract on cartilage. Biol Pharm Bull 33, 1004-1010 (2010)
doi:10.1248/bpb.33.1004
196. David, T. Felson, Reva, C. Lawrence, Marc, C. Hochberg, Timothy, McAlindon, Paul, A. Dieppe, Marian, A. Minor, Steven, N. Blair, Brian, M. Berman, James, F. Fries, Morris, Weinberger, Kate, R. Lorig, Joshua, J. Jacobs, Victor, Goldberg: Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med 133, 726-737 (2000)
197. Minns, Lowe Catherine, J., Barker, Karen L., Dewey, Michael E., Sackley, Catherine M.: Effectiveness of physiotherapy exercise following hip arthroplasty for osteoarthritis: a systematic review of clinical trials. BMC Musculoskelet Disord 10, 98 (2009)
doi:10.1186/1471-2474-10-98
PMid:19653883 PMCid:2734755
198. Forestier, R., Desfour, H., Tessier, J. M., Françon, A., Foote, A. M., Genty, C., Rolland, C., Roques, C. F., Bosson, J. L.: Spa therapy in the treatment of knee osteoarthritis, a large randomised multicentre trial. Ann Rheum Dis 69, 660-665 (2010)
doi:10.1136/ard.2009.113209
PMid:1973413
199. Takahashi, Kenji A., Tonomura, Hitoshi, Arai, Yuji, Terauchi, Ryu, Honjo, Kuniaki, Hiraoka, Nobuyuki, Hojo,Tatsuya, Kunitomo, Taisuke, Kubo, Toshikazu: Hyperthermia for the treatment of articular cartilage with osteoarthritis. Int J Hyperthermia 25, 661-667 (2009)
doi:10.3109/02656730903107519
PMid:19905896
200. Gremion, Gerald, Gaillard, David, Leyvraz, Pierrre-Francois, Jolles, Brigitte M: Effect of biomagnetic therapy versus physiotherapy for treatment of knee osteoarthritis: a randomized controlled trial. J Rehabil Med 41, 1090-1095 (2009)
doi:10.2340/16501977-0467
PMid:19894007
201. Haflah, Nor Hazla M., Jaarin, Kamsiah, Abdullah, Suhail, Omar, Masbah: Palm vitamin E and glucosamine sulphate in the treatment of osteoarthritis of the knee. Saudi Med J 30, 1432-1438 (2009)
PMid:19882056
202. Wang, Chenchen, Schmid, Christopher H., Hibberd, Patricia L., Kalish, Robert, Roubenoff, Ronenn, Rones, Ramel, Mcalindon, Timothy: Tai Chi is effective in treating knee osteoarthritis: A randomized controlled trial. Arthritis Rheum 61, 1545-1553 (2009)
doi:10.1002/art.24832
203. McAlindon, Timothy E., LaValley, Michael P., Gulin, Juan P., Felson, David T.: Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 283, 1469-1475 (2000)
PMid:17681803
204. Bruyere, O., Pavelka, K., Rovati, L. C., Gatterová, J., Giacovelli, G., Olejarová, M., Deroisy, R., Reginster, J. Y.: Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis Cartilage 16, 254-260 (2008)
doi:10.1016/j.joca.2007.06.011
205. Ronca, Francesca, Palmieri, Lina, Panicucci, Patrzia, Ronca, Giovanni: Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 6, 14-21 (1998)
doi:10.1016/S1063-4584(98)80006-X
206. Uebelhart, Daniel, Thonar, Eugene J-M. A., Zhang, Jinwen, Williams, James M.: Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit. Osteoarthritis Cartilage 6, 6-13 (1998)
doi:10.1016/S1063-4584(98)80005-8
207. Wen, Z. H., Tang, C. C., Chang, Y. C., Huang, S. Y., Hsieh, S. P., Lee, C. H., Huang, G. S., Ng, H. F., Neoh, C. A., Hsieh, C. S., Chen, W. F., Jean, Y. H.: Glucosamine sulfate reduces experimental osteoarthritis and nociception in rats: association with changes of mitogen-activated protein kinase in chondrocytes. Osteoarthritis Cartilage 18, 1192-1202 (2010)
doi:10.1016/j.joca.2010.05.012
PMid:10732937
208. Baici, Antonio, Bradamante, Paola: Interaction between human-leukocyte elastase and chondroitin sulfate. Chem Biol Interact 51, 1-11 (1984)
doi:10.1016/0009-2797(84)90015-2
209. De Gennaro, F., Piccioni, P. D., Caporali, R., Luisetti, M., Contecucco, C.: Effet du traitement par le sulfate de galactosaminoglucuronoglycane sur l'estase granulocytaire synovial de patients atteints d'osteoarthrose. Liter Rhumatologica 14, 53-60 (1992)
210. Reichenbach, Stephan, Sterchi, Rebekka, Scherer, Martin, Trelle, Sven, Burgi, Elizabeth, Burgi, Ulrich, Dieppe, Paul A., Juni, Peter: Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 146, 580-590 (2007)
PMid:17438317
211. Florent, Richy, Olivier, Bruyere, Olivier, Ethgen, Michel, Cucherat, Yves, Henrotin, Jean-Yves, Reginster: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 163, 1514-1522 (2003)
doi:10.1001/archinte.163.13.1514
PMid:12860572
212. McAlindon, T.: Glucosamine and chondroitin for osteoarthritis? B Rheum Dis 50, 1-4 (2001)
PMid:11530541
213. Black, C., Clar, C., Henderson, R., MacEachern, C., McNamee, P., Quayyum, Z., Royle, P., Thomas, S.: The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation. Health Technol Asses 3, 1-148 (2009)
214. Gupta, R. C., Canerdy, T. D., Skaggs, P., Stocker, A., Zyrkowski, G., Burke, R., Wegford, K., Goad, J. T., Rohde, K., Barnett, D., DeWees, W., Bagchi, M., Bagchi, D.: Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther 32, 577-584 (2009)
doi:10.1111/j.1365-2885.2009.01079.x
PMid:20444013
215. Crowley, David C., Lau, Francis C., Sharma, Prachi, Evans, Malkanthi, Guthrie, Najla, Bagchi, Manashi, Bagchi, Debasis, Dey, Dipak K., Raychaudhuri, Siba P.: Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci 6, 312-321 (2009)
PMid:19847319 PMCid:2764342
216. Phiphobmongkol, Vajara, Sudhasaneya, Vudhipong: The effectiveness and safety of intra-articular injection of sodium hyaluronate (500-730 kDa) in the treatment of patients with painful knee osteoarthritis. J Med Assoc Thai 92, 1287-1294 (2009)
PMid:19845235
217. Jørgensen, Anette, Stengaard-Pedersen, Kristian, Simonsen, Ole, Pfeiffer-Jensen, Mogens, Eriksen, Christian, Bliddal, Henning, Pedersen, Niels Wisbech, Bodtker, Soren, Hørslev-Petersen, Kim, Snerum, Lennart Ortoft, Egund, Niels, Frimer-Larsen, Helle: Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis 69, 1097-1102 (2010)
doi:10.1136/ard.2009.118042
PMid:20447955
218. Brouwer, Reinoud W., Raaij van, Tom M., Bierma-Zeinstra, Sita M. A., Verhagen, Arianne P., Jakma, T. S. C., Verhaar, Jan A. N.: Osteotomy for treating knee osteoarthritis. Cochrane Database Syst Rev 3, CD004019 (2007)
PMid:17636743
219. Virolainen, Petri, Aro, Hannu T.: High tibial osteotomy for the treatment of osteoarthritis of the knee: a review of the literature and a meta-analysis of follow-up studies. Arch Orthop Traum Su 124, 258-261 (2004)
doi:10.1007/s00402-003-0545-5
PMid:12827394
220. Strecker, W., Dickschas, J., Harrer, J., Müller, M.: Arthroscopy prior to osteotomy in cases of unicondylar osteoarthritis. Orthopade 38, 263-268 (2009)
doi:10.1007/s00132-008-1390-6
PMid:19242673
221. Spahn, Gunter, Mückley, Thomas, Kahl, Enrico, Hofmann, Gunther O.: Factors affecting the outcome of arthroscopy in medial-compartment osteoarthritis of the knee. Arthroscopy 22, 1233-1240 (2006)
doi:10.1016/j.arthro.2006.07.003
PMCid:287978
222. Helenius, I., Tanskanen, P., Haapala, J., Niskanen, R., Remes, V., Mokka, R., Korkala, O.: Hip arthroscopy in osteoarthritis. A review of 68 patients. Ann Chir Gynaecol 90, 28-31 (2001)
PMid:11336365
223. Goubiera, J. N., Bauer, B., Alnotb, J. Y., Teboul, F.: Scapho-trapezio-trapezoidal arthrodesis for scapho-trapezio-trapezoidal osteoarthritis. Chir Main 25, 179-184 (2006)
224. Jones, P., Delco, M., Beard, W., Lillich, J. D., Desormaux, A.: A limited surgical approach for pastern arthrodesis in horses with severe osteoarthritis. Vet Comp Orthop Traumatol 22, 303-308 (2009)
PMid:19597626
225. Raven, E. E. J., Kerkhoffs, G. M. M. J., Rutten, S., Marsman, A. J. W., Marti, R. K., Albers, G. H. R.: Long term results of surgical intervention for osteoarthritis of the trapeziometacarpal joint: comparison of resection arthroplasty, trapeziectomy with tendon interposition and trapezio-metacarpal arthrodesis. Int orthop 31, 547-554 (2007)
doi:10.1007/s00264-006-0217-5
PMid:17021835 PMCid:2267630
226. Glanzmann, Michael Christoph, Sanhueza-Hernandez, Roberto: Arthroscopic subtalar arthrodesis for symptomatic osteoarthritis of the hindfoot: a prospective study of 41 cases. Foot Ankle Int 28, 2-7 (2007)
doi:10.3113/FAI.2007.0001
227. Shin, Eon K, Jupiter, Jesse B.: Radioscapholunate arthrodesis for advanced degenerative radiocarpal osteoarthritis. Tech Hand Up Extrem Surg 11, 180-183 (2007)
doi:10.1097/BTH.0b013e3180413883
PMid:17805154
228. Kofoed, Hakon, Sørensen, Torben S.: Ankle arthroplasty for rheumatoid arthritis and osteoarthritis: prospective long-term study of cemented replacements. J Bone Joint Surg Br 80, 328-332 (1998)
doi:10.1302/0301-620X.80B2.8243
229. Marya, S. K. S., Thukral, Rajiv: Unicompartmental knee arthroplasty for tricompartment osteoarthritis in octogenarians. Indian J Orthop 43, 361-366 (2009)
doi:10.4103/0019-5413.54970
PMid:19838386 PMCid:2762558
230. Sandelin, J., Harilainen, A., Crone, H., Hamberg, P., Forsskahl, B., Tamelander, G.: Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol 26, 287-292 (1997)
doi:10.3109/03009749709105318
PMid:9310109
231. Hochberg, Marc C., Altman, Roy D., Brandt, Kenneth D., Clark, Bruce M., Dieppe, Paul A., Griffin, Marie R., Moskowitz, Roland W., Schnitzer, Thomas J.: Guidelines for the medical management of osteoarthritis. Part II. Osteoarthritis of the knee. American College of Rheumatology. Arthritis Rheum 38, 1541-1546 (1995)
doi:10.1002/art.1780381104
232. Connor, J.R.; LePage, C.; Swift, B.A.; Yamashita, D.; Bendele, A.M.; Maul, D.; Kumar, S.: Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis. Osteoarthritis Cartilage 17, 1236-1243 (2009)
doi:10.1016/j.joca.2009.03.015
PMid:19361586
233. Akasaki, Yukio, Matsuda, Shuichi, Iwamoto, Yukihide: Progress of Research for Osteoarthritis. The anti-inflammatory effects of intra-articular injected statin on experimental osteoarthritis. Clin Calcium 19, 1653-1662 (2009)
PMid:19880999
234. Liu, Yu Ping, Yu, Guang Rong: Comment on "The matrix metalloproteinases as pharmacological target in osteoarthritis: Statins may be of therapeutic benefit". Med Hypotheses 74, 394-395 (2010)
doi:10.1016/j.mehy.2009.09.050
PMid:19846258
235. Hsieh, Jeng Long, Shen, Po Chuan, Shiau, Ai Li, Jou, I. Ming, Lee, Che Hsin, Wang, Chrong Reen, Teo, Min Li, Wu, Chao Liang: Intraarticular gene transfer of thrombospondin-1 suppresses the disease progression of experimental osteoarthritis. J Orthop Res 28, 1300-1306 (2010)
doi: 10.1002/jor.21134
PMid:20309955
236. Cialdai, Cecilia, Giuliani, Sandro, Valenti, Claudio, Tramontana, Manuela, Maggi, Carlo Alberto: Effect of Intra-articular-4-(S)-Amino-5-(4-{4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl)(trimethyl)ammonium chloride hydrochloride (MEN16132), a Kinin B-2 Receptor Antagonist, on Nociceptive Response in Monosodium Iodoacetate-Induced Experimental Osteoarthritis in Rats. J Pharmacol Exp Ther 33, 1025-1032 (2009)
doi:10.1124/jpet.109.159657
PMid:19745108
237. Bar-Yehuda, S.; Rath-Wolfson, L.; Del Valle, L.; Ochaion, A.; Cohen, S.; Patoka, R.; Zozulya, G.; Barer, E.; Atar, E.; Pina-Oviedo, S.; Perez-Liz, G.; Castel, D.; Fishman, P.: Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis Rheum 6, 3061-3071 (2009)
doi:10.1002/art.24817
238. Karsdal, Morten A.; Sondergaard, Bodil C.; Arnold, Michel; Christiansen, Claus: Calcitonin affects both bone and cartilage: a dual action treatment for osteoarthritis? Ann N Y Acad Sci 1117, 181-195 (2007)
doi:10.1196/annals.1402.041
PMid:18056043
239. Tat, Steeve Kwan; Pelletier, Jean-Pierre; Velasco, Carmen Ruiz; Padrines, Marc; Martel-Pelletier, Johanne: New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target? Keio J Med 58, 29-40 (2009)
doi:10.2302/kjm.58.29
PMid:19398882
240. Nixon, A. J., Haupt, J. L., Frisbie, D. D., Morisset, S. S., McIlwraith, C. W., Robbins, P. D., Evans, C. H., Ghivizzani, S.: Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy. Gene Ther 12, 177-186 (2005)
doi:10.1038/sj.gt.3302396
PMid:15578043
241. Evans, C. H., Gouze, J. N., Gouze, E., Robbins, P. D., Ghivizzani, S. C.: Osteoarthritis gene therapy. Gene Ther 11, 379-389 (2004)
doi:10.1038/sj.gt.3302196
PMid:14724685
242. Hattori, Koji, Ohgushi, Hajime: Progress of Research for Osteoarthritis. Tissue engineering therapy for osteoarthritis. Clin Calcium 19, 1621-1628 (2009)
PMid:19880995
243. Zscharnack, Matthias, Hepp, Pierre, Richter, Robert, Aigner, Thomas, Schulz, Ronny, Somerson, Jeremy, Josten, Christoph, Bader, Augustinus, Marquass, Bastian: Repair of Chronic Osteochondral Defects Using Predifferentiated Mesenchymal Stem Cells in an Ovine Model. Am J Sports Med 38, 1857-1869 (2010)
doi:10.1177/0363546510365296
PMid:20508078
244. Loughlin, John: Genetic epidemiology of primary osteoarthritis. Curr Opin Rheumatol 13, 111-116 (2001)
doi:10.1097/00002281-200103000-00004
PMid:11224735
Abbreviations: OA: osteoarthritis, ECM: extracellular matrix, Col2a1: collagen type II, alpha 1, HIF-2alpha:hypoxia-inducible factor-2alpha, SNP: single nucleotide polymorphism, COL11A1: collagen type XI, alpha 1, SLRP: small-leucine-rich-proteoglycan, Agc1: aggrecan 1, TGF-beta: transforming growth factor beta, COMP: cartilage olgomeric matrix protein, MATN3: matrilin 3, FRZB: frizzled-related protein, CILP: cartilage intermediate-layer protein, VDR: vitamin D receptor, KL: koltho, ESR1: oestrogen receptor alpha, BMP: bone morphogenetic protein, OPG: osteoprotegerin, IL-1: interleukin 1, IL1R1: interleukin 1 receptor 1, PGE2: prostaglandin E2, COX2: cyclooxygenase 2,: TXNDC3: Thioredoxin domain containing 3, RHOB: Ras homolog gene family, member B, BLP2: BBP-like protein 2, CIAS1: cold auto-inflammatory syndrome 1, CD36: cluster of Differentiation 36, NCOR2: nuclear receptor co-repressor, DIO2: type II iodothyronine deildinase, TNA: tetranectin, MT-1-MMP: membrane type 1 matrix metalloproteinase, BGN: biglycan, FM: fibromodulin, Gdf5: growth differentiation factor 5, Hh: hedgehog, SmoM2: SMO homolog protein, TNF: tumor necrosis factor, Ca: calcium, P: phosphorus, Mg: magnesium, S: sulfur, K: potassium, GAG: glycosaminoglycan, ACLT: anterior cruciate ligament transaction, OSM: oncostatin M, MSCs: mesenchymal stem cells, MMPs: matrix metalloproteinases, TIMP: tissue Inhibitor of metalloproteinase, NO: nitric oxide, TRAP: Tartrate-resistant acid phosphatase, nfat2: nuclear factor of activated T cells 2, Oscar: osteoclast-associated receptor, ALP: alkaline phosphatase, IGF-1: insulin-like growth factor 1, EP: E prostanoid, PI3K/Akt: phosphatidylinositol 3-kinase, CTGF: connective tissue growth factor, FGFs: fibroblast growth factors, VEGF: vascular endothelial growth factor, RANKL: receptor activator of NF-kappaB ligand, TRAF3: TNF receptor-associated factor 3, OCPs: osteoclast precursors, SA-β-gal: senescence associated beta-gal, p53: tumor protein 53, p21: cyclin-dependent kinase inhibitor 1, p16: cyclin-dependent kinase inhibitor 2A, SOD2: superoxide dismutase 2, ROS: reactive oxygen species, ULK1: Unc-51-like kinase 1, LC3: light chain 3, Smad: proteins that modulate the activity of transforming growth factor beta ligands, Smurf-2: E3 ubiquitin-protein ligase, PTA: posttraumatic osteoarthritis, PG: proteoglycans, GADD45beta: growth arrest DNA damage 45 beta, WNT: wingless MMTV integration, IFP: infrapatellar fat pad, CD90: human Thy-1 antigen, SFs: synovial fibroblasts, TMJ: temporomandibular joint, HP: hydrostatic pressure, MDSCs: muscle-derived stem cells, sFlt-1: one of the VEGF antagonists, HrtA1: high-temperature requirement protein A1, PAR-2: proteinase-activated receptor, PCMO: programmable cell of monocytic origin, PLAP-1: periodontal ligament-associated protein-1, NSAIDs: Non-steroidal anti-inflammatory drugs, GI: gastrointestinal, RCTs: randomized controlled trials, HPE: human placenta extract, MIA: monoiodoacetate, MAPKs: mitogen-activated protein kinases, ERK: extracellular signal-regulated kinase, UC-II: undenatured type II collagen, TSP-1: thrombospondin-1
Key Words: Osteoarthritis, Gene, Animal model, Mechanisms, Therapies, Articular cartilage, Subchondral bone, Synovium, BMPs, Review
Send correspondence to: Yi-Ping Li, Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Blvd,Birmingham AL 35294-2182, Tel: 205 975-2606, Fax: 205-975-4919, E-mail:ypli@uab.edu