[Frontiers in Bioscience E3, 888-895, June 1, 2011]
The roles of adenosine and adenosine receptors in bone remodeling
Wenjie He, Bruce Cronstein
Division of Clinical Pharmacology, NYU School of Medicine, NYC, NY, US
TABLE OF CONTENTS
1. ABSTRACT
Adenosine regulates a wide variety of physiological processes including heart rate, vasodilation and inflammation through the activation of specific cell surface adenosine receptors. In addition to these well-established roles of adenosine, recent genetic and pharmacological research has implicated adenosine as an important regulator in bone remodeling. The secretion of adenosine and the presence of its four receptors in bone cells have been well documented. More recently, we provided the first evidence that adenosine regulates osteoclast formation and function through A1 receptor (A1R), and showed that A1R-knockout mice have significantly increased bone volume as a result of impaired osteoclast-mediated bone resorption. Moreover, adenosine A1R-knockout mice are protective from boss loss following ovariectomy further supporting the involvement of adenosine in osteoclast formation and function. This short review summarizes current knowledge related to the roles of adenosine and adenosine receptors in bone formation and remodeling. A deeper insight into the regulation of bone metabolism by adenosine receptors should assist in developing new therapies for osteoporosis.
2. INTRODUCTION
Bone remodeling is a process that takes place throughout life and is required not only for skeletal growth but also to maintain normal bone structure. Bone remodeling consists of coupled bone resorption by osteoclasts and bone formation by osteoblasts. If anything goes awry in this balance, as with advancing age or during disease conditions such as rheumatoid arthritis (RA), skeletal abnormalities will develop such as osteoporosis. Great progress has been made over the last decade in understanding the intercellular and intracellular processes that mediate and regulate osteoclastogenesis and osteoclast activity (1-11). Three molecules play central roles in the regulation of osteoclastogenesis: the receptor activator of NF-{kappa}b ligand (RANKL), a constitutive transmembrane protein on osteoblasts which is also present as a soluble mediator (1-5); RANK, the receptor for RANKL and (2, 6-8); the soluble natural decoy receptor for RANKL, osteoprotegerin (OPG) which is secreted from osteoblasts (9-11). The balance of RANKL and OPG regulates the extent and degree of osteoclastogenesis (12-13). Moreover, the dissection of these pathways indicates that the osteoblast communicates with osteoclast progenitors and regulates their differentiation into osteoclasts via both secretion of signaling molecules and by direct cell-cell interactions.
There is a growing body of evidence to suggest that bone resorption during inflammatory bone destruction is regulated by the immune system giving rise to a new field of research named osteoimmunology (14-17). The key player in the RANK-RANKL-OPG axis, RANKL, was originally identified as an activator of dendritic cells expressed by activated T cells (1-2). Another molecule that is secreted by T cells and has proven to be a regulator of osteoclastogenesis is interferon-gamma (IFN-gamma) (18). IFN-gamma promotes degradation of TNF receptor-associated factor 6 (TRAF6), a critical adaptor protein involved in RANKL signaling, via the ubiquitin-proteasome pathway (19). The signaling receptor for RANKL, RANK, expressed on osteoclast progenitors, is also abundant in dendritic cells and detectable in CD4+ and CD8+ T cells (20). Clearly, the identification of these molecules and the cells expressing them within the bone microenvironment will be critical to furthering our understanding of the regulation of osteoclastogenesis.
Because mature osteoclasts require high adenosine 5′-triphosphate (ATP) levels to support bone resorption and biosynthetic intermediates to supply many cellular constituents, the high turnover rate of ATP and its breakdown products, including adenosine, in osteoclasts also seems to play a role in regulating osteoclast differentiation (21-23). Based on our recent studies we propose that adenosine alterations are also important regulators of RANKL-stimulated osteoclast formation and differentiation. This review will summarize prior knowledge and recent developments in the area of adenosinergic regulation of bone remodeling.
3. ADENOSINE PRODUCTION AND EXPRESSION OF ADENOSINE RECEPTORS IN BONE
Adenosine is generally released from cells as a result of ATP catabolism. In stress situations like ischemia or hypoxia extracellular adenosine concentrations may be measured at micromolar concentrations due to a massive ATP degradation with minimal ATP regeneration leading to the release of adenosine through bidirectional cell surface nucleoside transporters. The other major pathway that contributes to high extracellular adenosine concentrations is the extracellular degradation of adenine nucleotides (ATP, ADP and AMP) to adenosine by a cascade of ectonucleotidases, including CD39 (nucleoside triphosphate phosphohydrolase) and CD73 (5'-ectonucleotidase). Adenosine exerts its action via the four types of receptors located on cell membranes and its accumulation is limited by its rapid catabolism to inosine by adenosine deaminase (ADA) outside of the cell or rephosphorylation to nucleotides within the cell.
When there is bone fracture or mechanical microdamage extracellular ATP in a lesion site can reach high concentrations (24-26). Since this purine nucleotide has a very short half-life and is known to be rapidly hydrolyzed to adenosine, it is reasonable to speculate an increase in levels of adenosine within the bone microenvironment. Accordingly, it has been described by Evans and colleagues in a recent study that human osteoblast precursor cell line, HCC1 and human primary bone marrow stromal cells (BMS) produce adenosine (27). We and others have clearly demonstrated that CD73 is expressed by both human and mouse mesenchymal progenitors that are capable of differentiating into osteoblasts (27-30). The study performed by Evans and colleagues confirmed that the CD73 expressed on HCC1 cells is a functional ectonucleotidase by comparing the degradation rates of exogenously added 1, N6-ethenoAMP in the presence and absence of the CD73 inhibitor, AOPCP (27). The same authors went on to suggest that adenosine acts in an autocrine fashion to modulate the activity of osteoblast precursors via A2b receptor which is activated only when the extracellular adenosine reaches high nanomolar to low micromolar levels. These observations indicate that osteoblast progenitors produce relative high levels of adenosine that likely acts on surrounding cells in bone and bone marrow, including osteoclast progenitors, in a paracrine manner (Figure 1).
Adenosine receptors are widely distributed on cells including inflammatory and immune cells and the cells of bone. Both the undifferentiated osteoblast precursor cells (HCC1 and BMS) and differentiated osteoblasts express all four receptors (A1, A2a, A2b and A3) (27-28). A mature osteoblast cell line, MG-63 expresses A1, A2a, and A2b receptors, but not the A3 receptor (31). Monocytes and macrophages also express adenosine receptors; for example, the mouse macrophage cell line RAW 264.7 which can be induced to osteoclastic differentiation in vitro by culturing with recombinant RANKL (32). Splenocytes and marrow-derived osteoclast progenitor cells also express adenosine receptors (32). All four adenosine receptors have been detected in these cells (32). Recent work from our laboratory has clearly revealed that mouse bone marrow-derived monocyte/macrophage precursor cells (BMMs) express all four receptors and A1 receptor is functionally predominant, as shown by the increased bone density in A1R-knockout mice and defective osteoclast differentiation in vitro by osteoclast progenitor cells from A1R-knockout mice (32-33). It is interesting to note here A1 receptor expression in BMMs is up-regulated during osteoclast differentiation (32). Adenosine receptors have also been described on a number of different mesenchymal cell types that are important in the pathophysiology of inflammatory knee osteoarthritis, including equine, human and bovine chondrocytes and fibroblast-like synoviocytes (34-39). Recent work has demonstrated that inflammatory cytokines, including TNF and IL-1, stimulate increased expression and function of adenosine receptors (40-42), a finding confirmed by recent studies that demonstrate that adenosine A2a and A3 receptors are up-regulated in both rheumatoid arthritis patients and that anti-TNF therapy leads to reduction of A2A receptor expression (43). Similarly, there is increased adenosine receptor expression on inflammatory cells in monosodium iodoacetate-induced osteoarthritic animal models (44). In these experiments, Bar-Yehuda et al. found CF101, a selective A3 agonist, prevented apoptosis of chondrocytes, which resulted in cartilage protection (44). Although it may be related to the anti-inflammatory properties of A3 receptors these studies highlight the potential significance of the adenosine receptors in osteoarthritis.
4. ADENOSINE AND OSTEOBLASTS
Early studies conducted by Shimegi and colleagues suggest that adenosine stimulates proliferation of osteoblast-like cells, the MC3T3-E1 osteoblastic cell line, although it is not as mitogenic as ATP and the receptor type involved was not addressed in these studies (45-46). Subsequent work has provided evidence for the importance of adenosine and adenosine receptors in osteoblast activity, although controversy exists regarding their roles (27, 31). Employing adenosine receptor analogues Evans and colleagues reported that adenosine modulates endogenous secretion of cytokines including interleukin 6 (IL-6) and OPG from HCC1 cells predominantly through A2b receptors (27). Russell et al. also describe adenosine receptor-dependence of cytokine expression from MG-63 cells, however, in contrast to Evans et al., they reported adenosine does not change the basal secretion of IL-6 from MG-63 cells. Instead adenosine attenuates lipopolysaccharide (LPS)-induced IL-6 release from osteoblast through A2a receptors, at least in part (31). The reasons for these discrepant results remain unclear, although they may reflect the peculiarities of these cell lines. It is interesting to note both studies suggest the involvement of cAMP/PKA signaling in the action of adenosine, a downstream signaling molecule for both A2a and A2b receptors (27, 31).
Although the effects of adenosine and its receptors on osteoblast remain to be clearly established, older studies in patients lacking adenosine deaminase (ADA) and a recent study with genetic mouse models strongly underlines the importance of adenosinergic regulation of osteoblast function (47-48). It was widely recognized that in children lacking adenosine deaminase there was bone dysmorphogenesis in addition to the clear immunodeficiency. By examining two immunodeficient mouse models, ADA-/- and Pag2 gamma c-/- which lack T, B and NK cells, Sauer and colleagues reported that a specific bone phenotype characterized by lower bone mass and impaired bone mechanical competence in ADA-/- mice is a consequence of alterations in purine metabolism (47). Their work further revealed the skeletal defects in ADA -/- mice are associated with markedly impaired osteoblast activity indicated by lower cell viability and reduced osteoblast-specific markers such as osteocalcin and N-terminal propeptide of type I procollagen (PINP) (47). It is noteworthy that the message level of Runx2, a key factor in osteogenesis, is normal in these ADA -/- mice, suggesting intact osteogenesis. Another intriguing finding is that ADA activity is 3-fold higher in mature wild type osteoblasts than in mesenchymal progenitor cells, further implicating the importance of adenosine in osteoblast function (47). In a recent study our group documented that osteoblast number and bone formation was unchanged in the bone of adenosine A1 receptor-KO mice, indicating that adenosine receptors other than A1R in regulate osteoblast formation and function in mice (33).
5. ADENOSINE AND OSTEOCLASTS
Osteoclasts are highly specialized bone-resorbing cells derived from myeloid precursors. They share several important features with immune cells. For example, nuclear factor of activated T cells (NFATc1), the key transcription factor leading to terminal differentiation of osteoclasts, was first identified in activated T cells (49-50). Indeed, activated T cells stimulate osteoclast formation in vitro (51-52). Recent work has discovered that osteoclasts and immune cells share a requirement for regulatory signals that are mediated by immunoreceptor tyrosine-based activation motif (ITAMs) (53-54). Two ITAM adaptor proteins, DNAX-activating protein 12 (DAP12) and Fc receptor common gamma subunit (FcR-gamma), are required for RANKL-induced osteoclast differentiation and bone resorption (53-54). Given the intertwined connection and similarity between osteoclasts and immune cells it is plausible to speculate that osteoclast might use similar mechanisms to regulate cellular development and function.
The hypothesis that adenosine receptors regulate osteoclasts has been supported by our recent finding that adenosine receptors regulate osteoclast formation and function, as the presence and function of adenosine receptors in monocyte and macrophage has been well established. Our studies utilizing A1R-knockout mice and pharmacological approaches clearly demonstrated that A1R contributes to osteoclast formation and function (32-33). We had previously observed that adenosine regulates the phorbol myristate acetate (PMA)-stimulated formation of multinucleated giant cells by cultured human peripheral blood monocytes through A1 receptors. 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), a specific inhibitor of the A1 receptor, almost completely abrogated phorbol ester-stimulated macrophage fusion into giant cells (55). Consistent with this observation, our more recent studies showed significantly increased trabecular and cortical bone density in 6-month-old A1KO mice compared with wild type (WT) mice (33). Morphologically, there were a normal number of osteoclasts in the bone but there was a marked loss of ruffled borders of the osteoclasts in A1R-knockout mice as compared with those from WT mice (33). In in vitro studies osteoclast formation was markedly impaired in BMMs isolated from A1KO animals when compared to WT controls (32). In addition, DPCPX potently inhibited the differentiation of osteoclast from WT BMMs and both blockade and deletion of adenosine A1 receptors diminished osteoclast bone resorption in vitro (32-33).
Regarding the regulatory mechanism of adenosine on osteoclast function, observation of adenosine production from osteoblast raises a question: does adenosine regulate the osteoclast formation and function in an autocrine and/or paracrine fashion? As a cue for resolving this question, our recently identified role of A1R in osteoclastogenesis suggests that adenosine may exert its action on osteoclast precursors in both manners. On one hand it can regulate the proliferation of osteoblast and secretion of cytokines from osteoblast, which in turn modifies osteoclastogenesis in a paracrine pathway. For example, IL-6 and OPG are both important regulators of osteoclastogenesis secreted by osteoblast in response to adenosine (10, 27, 56). On the other hand, adenosine generates a concentration gradient from osteoblast to osteoclast precursors in the bone microenvironment and regulates the osteoclast formation and function in an autocrine fashion. This pathway is mediated through binding to specific surface receptors (Figure 1).
6. ADENOSINE AND BONE HOMEOSTASIS
Since all four adenosine receptors may be expressed on the same cell or different cells in a tissue it is likely that the affinity of the various adenosine receptors for the ligand dictates which receptor's effects will predominate under specific conditions. In general the A1 receptor has the highest affinity for adenosine, followed by the A2a receptors. A2b and A3 receptors are lower affinity receptors. Thus, under basal, non-stressed conditions when adenosine concentrations are low the functional effects of A1 receptors will dominate. Modest stress or pharmacologic induction of adenosine will lead to A2a receptor predominance and severe stresses will lead to predominance of A2b or A3 receptor functions. Furthermore, the finding that adenosine receptors regulate both osteoclast function and inflammatory process reveals a potential network of signaling cross-talk between osteoclast resorption and immune system. These findings suggest that osteoclasts are indeed highly regulated by multiple factors simultaneously, which can partially explain the inability of some early experiments to demonstrate an effect of adenosine on osteoclasts or the apparent normality of osteoclast formation in vitro with macrophage colony- stimulating factor (M-CSF)/RANKL-treated precursors ADA deficient mice (47, 57). To understand the precise roles of adenosine and adenosine receptors further studies detailing the analysis of bone phenotypes of knockout mice deficient in individual adenosine receptors will be required.
7. THERAPEUTIC IMPLICATIONS
Our recent studies in models of osteoporosis indicate that adenosine A1 receptors may be useful targets for the treatment or prevention of osteoporosis since both deletion and pharmacologic blockade of A1 receptors prevented osteoporosis following ovariectomy (32-33). Pharmacological blockade of the A1R may also be a useful target in treating diseases characterized by excessive bone turnover such as osteoporosis, prosthetic joint loosening and other conditions in which osteoclasts play a pathogenic role (e.g. Paget's disease).
The studies discussed here clearly suggest that agents that promote, directly or indirectly, activation of adenosine receptors on cells of the bone and joint might be useful in the treatment of inflammatory joint and bone diseases such as rheumatoid arthritis. Indeed, evidence suggests that we are already targeting adenosine receptors in the treatment of inflammatory bone and joint treatments. Thus, our laboratory and others have shown that the antiinflammatory effects of low-dose methotrexate, the anchor drug in the treatment of rheumatoid arthritis and other forms of inflammatory arthritis, are mediated by adenosine (58-59). Methotrexate inhibits inflammatory bone destruction both in animal models of inflammatory arthritis and in patients with inflammatory arthritis and it is likely that adenosine, acting at its receptors, plays a role in suppression of bone injury in this setting although it is not clear at present whether this effect is direct or indirect via reduction in inflammation (60-62).
Thus it is likely that adenosine receptors may be targeted for the treatment of bone diseases and the bone manifestations of inflammatory diseases. The utility of adenosine receptors as targets for the treatment of bone disease will require a great deal more studies.
8. REFERENCES
1. Brian R. Wong, Jaerang Rho, Joseph Arron, Elizabeth Robinson, Jason Orlinick, Moses Chao, Sergey Kalachikovi, Eftihia Cayanii, Frederick S. Bartlett III, Wayne N. Frankel, Soo Young Lee and Yongwon Cho: TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun n-terminal kinase in T cells. J Biol Chem 272, 25190-25194 (1997)
doi:10.1074/jbc.272.40.25190
PMid:9312132
2. Dirk M. Anderson, Eugene Marakovsky, William L. Billingsley, William C. Dougall, Mark E. Tometsko, Eileen R. Roux, Mark C. Teepe, Robert F. DuBose, Davide Cosman and Laurent Galibert: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179 (1997)
doi:10.1038/36593
PMid:9367155
3. Hisataka Yasuda, Nobuyuki Shima, Nobuaki Nakagawa, Kyoji Yamaguchi, Masahiko Kinosaki, Shin-Ichi Mochizuki, Akihiro Tomoyasu, Kazuki Yano, Masaaki Goto, Akihiko Murakami, Eisuke Tsuda, Tomonori Morinaga, Kanji Higashio, Nobuyuki Udagawa, Naoyuki Takahashi and Tatsuo Suda: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95, 3597-35602 (1998)
doi:10.1073/pnas.95.7.3597
4. Young-Yun Kong, Hiroki Yoshida, Ildiko Sarosi, Hong-Lin Tan, Emma Timms, Casey Capparelli, Sean Morony, Antonio J. Oliveira-dos-Santos, Gwyneth Van, Annick Itie, Wilson Khoo, Andrew Wakeham, Colin R. Dunstan, David L. Lacey, Tak W. Mak, William J. Boyle and Josef M. Penninger: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323 (1999)
doi:10.1038/16852
PMid:9950424
5. D. L. Lacey, E. Timms, H.-L. Tan, M. J. Kelley, C. R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, H. Hsu, J. Sullivan, N. Hawkins, E. Davy, C. Capparelli, A. Eli, Y.-X. Qian, S. Kaufman, I. Sarosi, V. Shalhoub, G. Senaldi, J. Guo, J. Delaney and W. J. Boyle: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-176 (1998)
PMid:9878548
6. Nobuaki Nakagawa, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki Shima, Hisataka Yasuda, Kazuki Yano, Tomonori Morinaga and Kanji Higashio: RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 253, 395-400 (1998)
doi:10.1006/bbrc.1998.9788
7. Hailing Hsu, David L. Lacey, Colin R. Dunstan, Irina Solovyev, Anne Colombero, Emma Timms, Hong-Lin Tan, Gary Elliott, Michael J. Kelley, Ildiko Sarosi, Ling Wang, Xing-Zhong Xia, Robin Elliott, Laura Chiu, Tabitha Black, Sheila Scully, Casey Capparelli, Sean Morony,Grant Shimamoto, Michael B. Bass and William J. Boyle: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96, 3540-3545 (1999)
doi:10.1073/pnas.96.7.3540
8. Ji Li, Ildiko Sarosi, Xiao-Qiang Yan, Sean Morony, Casey Capparelli, Hong-Lin Tan, Susan McCabe, Robin Elliott, Sheila Scully, Gwyneth Van, Stephen Kaufman, Shao-Chieh Juan,Yu Sun, John Tarpley, Laura Martin, Kathleen Christensen, James McCabe, Paul Kostenuik, Hailing Hsu, Frederick Fletcher, Colin R. Dunstan, David L. Lacey and William J. Boyle: RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97, 1566-1571 (2000)
doi:10.1073/pnas.97.4.1566
PMid:9492069
9. Hisataka Yasuda, Nobuyuki Shima, Nobuaki Nakagawa, Shin-Ichi Mochizuki, Kazuki Yano, Nobuaki Fujise, Yasushi Sato, Masaaki Goto, Kyoji Yamaguchi, Masayoshi Kuriyama, Takeshi Kanno, Akihiko Murakami, Eisuke Tsuda, Tomonori Morinaga and Kanji Higashio: Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139, 1329-1337 (1998)
doi:10.1210/en.139.3.1329
PMid:9168977
10. Eisuke Tsuda, Masaaki Goto, Shin-ichi Mochizuki, Kazuki Yano, Fumie Kobayashi, Tomonori Morinaga and Kanji Higashio: Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 234, 137-142 (1997)
doi:10.1006/bbrc.1997.6603
PMid:9794488
11. W. S. Simonet, D. L. Lacey, C. R. Dunstan, M. Kelley, M.-S. Chang, R. Lüthy, H. Q. Nguyen, S. Wooden, L. Bennett, T. Boone, G. Shimamoto, M. DeRose, R. Elliott, A. Colombero, H.-L. Tan, G. Trail, J. Sullivan, E. Davy, N. Bucay, L. Renshaw-Gegg, T. M. Hughes2, D. Hill, W. Pattison, P. Campbell, S. Sander, G. Van, J. Tarpley, P. Derby, R. Lee and W. J. Boyle: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309-319 (1997)
PMid:10208850
12. Nicole J. Horwood, Jan Elliott, T. John Martin and Matthew T. Gillespie: Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139, 4743-4746 (1998)
doi:10.1210/en.139.11.4743
PMid:10580503
13. Masazumi Nagai and Nobuko Sato: Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation. Biochem Biophys Res Commun 257, 719-723(1999)
doi:10.1006/bbrc.1999.0524
PMid:7481803
14. Young-Yun Kong, Ulrich Feige, Iidiko Sarosi, Brad Bolon, Anna Tafuri, Sean Morony, Casey Capparelli, Ji Li, Robin Elliott, Susan McCabe, Thomas Wong, Giuseppe Campagnuolo, Erika Moran, Earl R. Bogoch, Gwyneth Van, Linh T. Nguyen, Pamela S. Ohashi, David L. Lacey, Eleanor Fish, William J. Boyle and Josef M. Penninger. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304-309 (1999)
doi:10.1038/46303
PMid:17088434 PMCid:2118166
15. Paul Waterhouse, Josef M. Penninger, Emma Timms, Andrew Wakeham, Arda Shahinian, Kelvin P. Lee, Craig B. Thompson, Henrik Griesser, Tak W. Mak: Lymphoproliferative disorders with early lethality inmice deficient in Ctla-4. Science 270, 985-988 (1995)
doi:10.1126/science.270.5238.985
PMid:11160187
16. Kojiro Sato, Ayako Suematsu, Kazuo Okamoto, Akira Yamaguchi, Yasuyuki Morishita, Yuho Kadono, Sakae Tanaka, Tatsuhiko Kodama, Shizuo Akira, Yoichiro Iwakura, Daniel J. Cua and Hiroshi Takayanagi: Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203, 2673-2682 (2006)
doi:10.1084/jem.20061775
PMid:17173138 PMCid:1697800
17. Theodore J. Yun, Michelle D. Tallquist, Alexandra Aicher, Katherine L. Rafferty, Aaron J. Marshall, James J. Moon, Maria K. Ewings, Mariette Mohaupt, Susan W. Herring and Edward A. Clark. Osteoprotegerin, a crucial regulator of bonemetabolism, also regulates B cell development and function. J Immunol 166, 1482-1491 (2001)
PMid:11117749
18. Yuhao Gao, Francesco Grassi, Michaela Robbie Ryan, masakazu Terauchi, Karen Page, Xiaoying Yang, Neale M. Weitzmann and Roberto Pacific: IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest 117, 122-132 (2007).
doi:10.1172/JCI30074
PMid:10072496
19. Hiroshi Takayanagi, Kouetsu Ogasawara, Shigeaki Hida, Tomoki Chiba, Shigeo Murata, Kojiro Sato, Akinori Takaoka, Taeko Yokochi, Hiromi Oda, Keiji Tanaka, Kozo Nakamura and Tadatsugu Taniguchi: T-cell-mediated regulation of osteoclastogenesis by signaling cross-talk between RANKL and IFN-γ. Nature 408, 600-605 (2000)
doi:10.1038/35046102
PMid:9706025 PMCid:2231120
20. Régis Josien, Brian R. Wong, Hong-Li Li, Ralph M. Steinman and Yongwon Choi: TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 162, 2562-2568 (1999)
PMid:11344082
21. Matthew S. Morrison, Luca Turin, Brian F. King, Geoffrey Burnstock and Timothy R. Arnett: ATP is a potent stimulator of the activation and formation of rodent osteoclasts. J Physiol 511, 495-500 (1998)
doi:10.1111/j.1469-7793.1998.495bh.x
22. K. A. Buckley, R. A. Hipskind, A. Gartland, W. B. Bowler and J. A. Gallagher: Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-kappa B ligand. Bone 31, 582-590 (2002)
PMid:12890693
23. Astrid Hoebertz, Sajeda Meghji, Geoffrey Burnstock and Timothy R. Arnett: Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y1 receptor on bone cells. FASEB J 15, 1139-1148 (2001)
doi:10.1096/fj.00-0395com
24. J. Buchholz, F. X. Huber, P. J. Meeder, G. Muhr, G. K. Kreitz and L. Herzog: Detection of high-energy phosphates in cortical bone as an indicator of bone healing and remodelling: Use of a rabbit model. J Orthop Surg (Hong Kong) 12, 205-209 (2004)
PMid:16418778
25. K. A. Buckley, S. L. Golding, J. M. Rice, J. P. Dillon, J. A. Gallagher. Release and interconversion of P2 receptor agonists by human osteoblast-like cells. FASEB J 17, 1401-1410 (2003)
doi:10.1096/fj.02-0940com
26. Damian C Genetos, Derik J Geist, Dawei Liu, Henry J Donahue and Randall L Duncan: Fluid shear-induced ATP secretion mediates postaglandin release in MC3T3-E1 osteoblasts. J Bone Miner Res 20, 41-49 (2005)
PMid:11716504
27. Bronwen A. J. Evans, Carole Elford, Annette Pexa, Karen Francis, Alis C Hughes, Andreas Deussen, and Jack Ham: Human osteoblast precursors produce extracellular adenosine, which modulates their secretion of IL-6 and osteoprotegerin. J Bone Miner Res 21, 228-236 (2006)
doi:10.1359/JBMR.051021
PMid:19056861
28. Bronwen A.J. Evans and Jack Ham: The role of adenosine in bone: an emerging concept. Immun Endoc Metab Agents in Med Chem 7, 322-327 (2007)
PMid:17705048
29. Frank Barry, Raymond Boynton, Mary Murphy and Joseph Zaia: The SH-3 and SH-4 antibodies recognize distinct epitopes on CD73 from human mesenchymal stem cells. Biochem Biophys Res Commun 289, 519-524 (2001)
doi:10.1006/bbrc.2001.6013
PMid:20181934
30. Majid Katebi, Mansooreh Soleimani and Bruce N. Cronstein: Adenosine A2a receptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. J Leukoc Biol 85, 438-444 (2009)
doi:10.1189/jlb.0908520
31. Joseph M. Russell, Graham S. Stephenson, Clare E. Yellowley and Hilary P. Benton: Adenosine inhibition of lipopolysaccharide-induced interleukin-6 secretion by the osteoblastic cell line MG-63. Calcif Tissue Int 81, 316-326 (2007)
doi:10.1007/s00223-007-9060-y
PMid:17698373
32. Firas M. Kara, Violeta Chitu, Jennifer Sloane, Matthew Axelrod, Bertil B. Fredholm, Richard E. Stanley and Bruce N. Cronstein: Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J 24, 2325-2333 (2010)
doi:10.1096/fj.09-147447
33. Firas M. Kara, Stephen B. Doty, Adele Boskey, Steven Goldring, Mone Zaidi, Bertil B. Fredholm and Bruce N. Cronstein: Adenosine A1 receptors regulate bone resorption in mice: adenosine A1 receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A1 receptor-knockout mice. Arthritis Rheum 62, 534-541 (2010)
doi:10.1002/art.27219
PMid:20331607
34. K. Varani, M. De Mattei, F. Vincenzi, S. Gessi, S. Merighi, A. Pellati, A. Ongaro, A. Caruso, R. Cadossi and P. A. Borea: Characterization of adenosine receptors in bovine chondrocytes and fibroblast-like synoviocytes exposed to low frequency low energy pulsed electromagnetic fields. Osteoarthritis Cargilage 16, 292-304 (2008)
doi:10.1016/j.joca.2007.07.004
PMid:11843119
35. Mitchell Koolpe, David Pearson and Hilary P. Benton: Expression of both P1 and P2 purine receptor genes by human articular chondrocytes and profile of ligand-mediated prostaglandin E2 release. Arthritis Rheum 42, 258-267 (1999)
doi:10.1002/1529-0131(199902)42:2<258::AID-ANR7>3.0.CO;2-O
PMid:16443378
36. K. Varani, F. Vincenzi, A. Tosi, M. Targa, F. F. Masieri, A. Ongaro, M. De Mattei, L. Massari and P. A. Borea: Expression and functional role of adenosine receptors in regulating inflammatory responses in human synoviocytes. Br J Pharmacol 160, 101-115 (2010)
doi:10.1111/j.1476-5381.2010.00667.x
37. Hilary P. Benton, Melinda H. MacDonald and Anthony M. Tesch: Effects of adenosine on bacterial lipopolysaccharide- and interleukin 1-induced nitric oxide release from equine articular chondrocytes. Am J Vet Res 63, 204-210 (2002)
doi:10.2460/ajvr.2002.63.204
PMid:11564822
38. D. Mistry, M. G. Chambers and R. M. Mason: The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line. Osteoarthritis Cartilage 14, 486-495 (2006)
doi:10.1016/j.joca.2005.11.015
39. David L. Boyle, Fereydoun G. Sajjadi and Gary S. Firestein: Inhibition of synoviocyte collagenase gene expression by adenosine receptor stimulation. Arthritis Rheum 39, 923-930 (1996)
doi:10.1002/art.1780390608
PMid:16385076 PMCid:1534129
40. Nguyen D. Khoa, Carmen M. Montesinos, Allison B. Reiss, David Delano, Nahel Awadallah and Bruce N. Cronstein: Inflammatory cytokines regulate function and expression of adenosine A(2A) receptors in human monocytic THP-1 cells. J Immunol 167, 4026-4032 (2001)
41. Nguyen D. Khoa, Carmen M. Montesinos, Adrienne J. Williams, Maureen Kelly and Bruce N. Cronstein: Th1 cytokines regulate adenosine receptors and their downstream signaling elements in human microvascular endothelial cells. J Immunol 171, 3991-3998 (2003)
42. Nguyen D. Khoa, Michael Postow, Jennifer Danielsson and Bruce N. Cronstein: Tumor necrosis factor-alpha prevents desensitization of Galphas-coupled receptors by regulating GRK2 association with the plasma membrane. Mol Pharmacol 69, 1311-1319 (2006)
doi:10.1124/mol.105.016857
PMid:9541519
43. Katia Varani, Alfonso Massara, Fabrizio Vincenzi, Alice Tosi, Melissa Padovan, francesco Trotta and Pier Andrea Borea: Normalization of A2a and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor α but not methotrexate. Arthritis Rheum 60, 2880-2891 (2009)
doi:10.1002/art.24794
PMid:8998680
44. S. Bar-Yehuda, L. Rath-Wolfson, L. Del Valle, A. Ochaion, S. Cohen, R. Patoka, G. Zozulya, F. Barer, E. Ata, S. Pina-Oviedo, G. Perez-Liz, D. Castel and P. Fishman: Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis Rheum 60, 3061-3071 (2009)
doi:10.1002/art.24817
PMid:19633200
45. S. Shimegi: Mitogenic action of adenosine on osteoblast-like cells, MC3T3-E1. Calcif Tissue Int 62, 418-425 (1998)
doi:10.1007/s002239900454
PMid:9801258
46. S. Shimegi: ATP and adenosine act as a mitogen for osteoblast-like cells (MC3T3-E1). Calcif Tissue Int 58, 109-113 (1996)
doi:10.1007/BF02529732
47. Aisha V. Sauer, Emanuela Mrak, Raisa Jofra Hernandez, Elena Zacchi, Francesco Cavani, Miriam Casiraghi, Eyal Grunebaum, Chaim M. Roifman, Maria C. Cervi, Alessandro Ambrosi, Filippo Carlucci, Maria Grazia Roncarolo, Anna Villa, Alessandro Rubinacci, and Alessandro Aiuti: ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood 114, 3216-3226 (2009)
doi:10.1182/blood-2009-03-209221
48. Michael S. Hershfield. Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol 35, 291-298 (1998)
PMid:9568710
49. Hiroshi Takayanagi, Sunhwa Kim, Takako Koga, Hiroshi Nishina, Masashi Isshiki, Hiroki Yoshida, Akio Saiura, Miho Isobe, Taeko Yokochi, Jun-ichiro Inoue, Erwin F. Wagner, Tak W. Mak, Tatsuhiko Kodama and Tadatsugu Taniguchi: Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3, 889-901 (2002)
doi:10.1016/S1534-5807(02)00369-6
PMid:9108485
50. Jeng-pyng Shaw, Paul J. utz, david B. Durand, J. Jay Toole, Elizabeth Ann Emmel and Gerald R. Crabtree: Identification of a putative regulator of early T cell activation genes. Science 241, 202-205 (1988)
PMid:12477572
51. Nicole J. Horwood, Vicky Kartsogiannis, Julian M.W. Quinn, Evangelos Romas, T.John Martin and Matthew T. Gillespie: Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 265, 144-150 (1999)
doi:10.1006/bbrc.1999.1623
PMid:10548505
52. Silvia Colucci, Giacomina Brunetti, Rita Rizzi, Antonia Zonno, Giorgio Mori, Graziana Colaianni, Davide Del Prete, Roberta Faccio, Arcangelo Liso, Silvana Capalbo, Vincenzo Liso, Alberta Zallone, and Maria Grano: T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction Blood 104, 3722-3730 (2004)
doi:10.1182/blood-2004-02-0474
PMid:15308561
53. Takako Koga, Masanori Inui, Kazuya Inoue, Sunhwa Kim, Ayako Suematsu, Eiji Kobayashi, Toshio Iwata, Hiroshi Ohnishi, Takashi Matozaki, Tatsuhiko Kodama, Tadatsugu Taniguchi, Hiroshi Takayanagi and Toshiyuki Takai: Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758-763 (2004)
doi:10.1038/nature02444
PMid:15085135
54. Attila Mócsai, Mary Beth Humphrey, Jessica A. G. Van Ziffle, Yongmei Hu, Andrew Burghardt, Steven C. Spusta, Sharmila Majumdar, Lewis L. Lanier, Clifford A. Lowell, and Mary C. Nakamura: The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci U S A 101, 6158-6163 (2004)
doi:10.1073/pnas.0401602101
PMid:15073337 PMCid:395939
55. Joan T. Merrill, Christine Shen, David Schreibman, Dan Coffey, Olga Zakharenko, Robert Fisher, Robert G. Lahita, Jane Salmon and Bruce N. Cronstein: Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum 40, 1308-1315 (1997)
PMid:9214432
56. Fumio Yoshitake, Shousaku Itoh, Hiroko Narita, Katsuhiko Ishihara and Shigeyuki Ebisu: Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-κB signaling pathways. J Biol Chem 283, 11535-11540 (2008)
doi:10.1074/jbc.M607999200
PMid:18296709
57. Ulf Lerner and Bertil B. Fredholm: 2-chloroadenosine increases calcium mobilization from mouse calvaria in vitro. Acta Endocrinol (Copenh) 100, 313-320 (1982)
58. Bruce N. Cronstein, Mark A. Eberle, Harry E. Gruber and Richard I. Levin: Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 88, 2441-2445 (1991)
doi:10.1073/pnas.88.6.2441
59. Hiroshi Asako, Robert E. Wolf and Neil D. Granger: Leukocyte adherence in rat mesenteric venules: effects of adenosine and methotrexate. Gastroenterology 104, 31-37 (1993)
PMid:8380395
60. Benoit Le Goff, Elise Soltner, Celine Charrier, yves Maugars, Francoise Redini, Dominique Heymann and Jean-Marie Berthelot: A combination of methotrexate and zoledronic acid prevents bone erosins and systemic bone mass loss in collagen induced arthritis. Arthritis Res Ther 11, R185 (2009)
61. Vibeke Strand, Stanley Cohen, Michael Schiff, Arthur Weaver, Roy Fleischmann, Grant Cannon, Robert Fox, Larry Moreland, Nancy Olsen, Dan Furst, Jacque Caldwell, Jeffrey Kaine, John Sharp, Frank Hurley, Iris Loew-Friedrich: Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 159, 2542-2550 (1999)
doi:10.1001/archinte.159.21.2542
PMid:10573044
62. Axel Finckh, Julia F. Simard, Jeffrey Duryea, Matthew H. Liang, Jie Huang, Synove Daneel, Adrian Forster, Cem Gabay and Pierre-Andre Guerne: The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study. Arthritis Rheum 54, 54-59 (2006)
doi:10.1002/art.21491
Abbreviations: A1R: A1 receptor, RANKL: the receptor activator of NF-κb ligand , OPG: osteoprotegerin, RA: rheumatoid arthritis, TRAF6: TNF receptor-associated factor 6, IFN- γ: interferon- γ, ATP: adenosine 5′-triphosphate, CD39: nucleoside triphosphate phosphohydrolase, CD73: 5'-ectonucleotidase, ADA: adenosine deaminase, BMS: marrow stromal cells, BMMs: bone marrow-derived monocyte/macrophage precursor cells, LPS: lipopolysaccharide, IL-6: interleukin 6, NFATc1: the nuclear factor of activated T cells, ITAMs: immunoreceptor tyrosine-based activation motif, DAP12: DNAX-activating protein 12, FcR-γ: Fc receptor common γ subunit, PMA: phorbol myristate acetate, DPCPX: 8-cyclopentyl-1, 3-dipropylxanthine, PINP: N-terminal propeptide of type I procollagen, M-CSF: macrophage colony- stimulating factor, RA: rheumatoid arthritis
Key Words: Adenosine, Adenosine receptors, Osteoclast, Osteoblast, Bone, Review
Send correspondence to: Brunce N. Cronstein, New York University School of Medicine, 550 First Avenue, NBV 16N1, New York, NY 10016, Tel: 212-263-6404, Fax: 212-263-1048, E-mail:cronsb01@med.nyu.edu