IMMUNE NETWORK

  • 제19권1호
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  • Pages.2.1-2.13
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  • 2019
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis

  • Youn-Kwan Jung (Biomedical Research Institute, Gyeongsang National University Hospital) ;
  • Young-Mo Kang (Division of Rheumatology, Department of Internal medicine, Kyungpook National University Hospital) ;
  • Seungwoo Han (Division of Rheumatology, Department of Internal medicine, Kyungpook National University Hospital)
  • 투고 : 2018.12.29
  • 심사 : 2019.02.17
  • 발행 : 2019.02.28
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초록

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4+ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

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과제정보

This research was supported by a grant to S.H. from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant numbers NRF-2016R1D1A1B03932036).

참고문헌

  1. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 2012;8:656-664. https://doi.org/10.1038/nrrheum.2012.153
  2. Odegard S, Landewe R, van der Heijde D, Kvien TK, Mowinckel P, Uhlig T. Association of early radiographic damage with impaired physical function in rheumatoid arthritis: a ten-year, longitudinal observational study in 238 patients. Arthritis Rheum 2006;54:68-75. https://doi.org/10.1002/art.21548
  3. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A 1990;87:7260-7264. https://doi.org/10.1073/pnas.87.18.7260
  4. Rivollier A, Mazzorana M, Tebib J, Piperno M, Aitsiselmi T, Rabourdin-Combe C, Jurdic P, Servet-Delprat C. Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood 2004;104:4029-4037. https://doi.org/10.1182/blood-2004-01-0041
  5. Bugatti S, Caporali R, Manzo A, Vitolo B, Pitzalis C, Montecucco C. Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment. Arthritis Rheum 2005;52:3448-3459. https://doi.org/10.1002/art.21377
  6. Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M, Dijkmans BA. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum 2004;50:36-42. https://doi.org/10.1002/art.11481
  7. Jones DH, Kong YY, Penninger JM. Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 2002;61 Suppl 2:ii32-ii39. https://doi.org/10.1136/ard.61.suppl_2.ii32
  8. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011;17:1231-1234. https://doi.org/10.1038/nm.2452
  9. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med 2011;17:1235-1241. https://doi.org/10.1038/nm.2448
  10. Meednu N, Zhang H, Owen T, Sun W, Wang V, Cistrone C, Rangel-Moreno J, Xing L, Anolik JH. Production of RANKL by memory B cells: a link between B cells and bone erosion in rheumatoid arthritis. Arthritis Rheumatol 2016;68:805-816. https://doi.org/10.1002/art.39489
  11. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006;203:2673-2682. https://doi.org/10.1084/jem.20061775
  12. Davidson MG, Alonso MN, Yuan R, Axtell RC, Kenkel JA, Suhoski MM, Gonzalez JC, Steinman L, Engleman EG. Th17 cells induce Th1-polarizing monocyte-derived dendritic cells. J Immunol 2013;191:1175-1187. https://doi.org/10.4049/jimmunol.1203201
  13. Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-α and IL-17. Rheumatology (Oxford) 2008;47:1635-1640. https://doi.org/10.1093/rheumatology/ken363
  14. Boumans MJ, Thurlings RM, Yeo L, Scheel-Toellner D, Vos K, Gerlag DM, Tak PP. Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis. Ann Rheum Dis 2012;71:108-113. https://doi.org/10.1136/annrheumdis-2011-200198
  15. Wheater G, Hogan VE, Teng YK, Tekstra J, Lafeber FP, Huizinga TW, Bijlsma JW, Francis RM, Tuck SP, Datta HK, et al. Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis. Osteoporos Int 2011;22:3067-3072. https://doi.org/10.1007/s00198-011-1607-0
  16. Danks L, Komatsu N, Guerrini MM, Sawa S, Armaka M, Kollias G, Nakashima T, Takayanagi H. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis 2016;75:1187-1195. https://doi.org/10.1136/annrheumdis-2014-207137
  17. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009;5:667-676. https://doi.org/10.1038/nrrheum.2009.217
  18. Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 2004;428:758-763. https://doi.org/10.1038/nature02444
  19. Herman S, Muller RB, Kronke G, Zwerina J, Redlich K, Hueber AJ, Gelse H, Neumann E, Muller-Ladner U, Schett G. Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum 2008;58:3041-3050. https://doi.org/10.1002/art.23943
  20. Crotti TN, Dharmapatni AA, Alias E, Zannettino AC, Smith MD, Haynes DR. The immunoreceptor tyrosine-based activation motif (ITAM)-related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints. Arthritis Res Ther 2012;14:R245.
  21. Barrow AD, Raynal N, Andersen TL, Slatter DA, Bihan D, Pugh N, Cella M, Kim T, Rho J, Negishi-Koga T, et al. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J Clin Invest 2011;121:3505-3516.  https://doi.org/10.1172/JCI45913
  22. Schultz HS, Guo L, Keller P, Fleetwood AJ, Sun M, Guo W, Ma C, Hamilton JA, Bjorkdahl O, Berchtold MW, et al. OSCAR-collagen signaling in monocytes plays a proinflammatory role and may contribute to the pathogenesis of rheumatoid arthritis. Eur J Immunol 2016;46:952-963. https://doi.org/10.1002/eji.201545986
  23. Schultz HS, Nitze LM, Zeuthen LH, Keller P, Gruhler A, Pass J, Chen J, Guo L, Fleetwood AJ, Hamilton JA, et al. Collagen induces maturation of human monocyte-derived dendritic cells by signaling through osteoclast-associated receptor. J Immunol 2015;194:3169-3179. https://doi.org/10.4049/jimmunol.1402800
  24. Braun T, Zwerina J. Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis Res Ther 2011;13:235.
  25. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106:1481-1488. https://doi.org/10.1172/JCI11176
  26. Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. J Exp Med 2012;209:319-334. https://doi.org/10.1084/jem.20111566
  27. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, et al. Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 2000;191:275-286. https://doi.org/10.1084/jem.191.2.275
  28. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN, et al. 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 1997;272:25190-25194. https://doi.org/10.1074/jbc.272.40.25190
  29. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390:175-179. https://doi.org/10.1038/36593
  30. O'Brien W, Fissel BM, Maeda Y, Yan J, Ge X, Gravallese EM, Aliprantis AO, Charles JF. RANK-independent osteoclast formation and bone erosion in inflammatory arthritis. Arthritis Rheumatol 2016;68:2889-2900. https://doi.org/10.1002/art.39837
  31. Kim JH, Jin HM, Kim K, Song I, Youn BU, Matsuo K, Kim N. The mechanism of osteoclast differentiation induced by IL-1. J Immunol 2009;183:1862-1870. https://doi.org/10.4049/jimmunol.0803007
  32. Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum 2009;60:2747-2756. https://doi.org/10.1002/art.24781
  33. Santiago MB, Galvao V. Jaccoud arthropathy in systemic lupus erythematosus: analysis of clinical characteristics and review of the literature. Medicine (Baltimore) 2008;87:37-44. https://doi.org/10.1097/MD.0b013e3181632d18
  34. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008;118:3537-3545. https://doi.org/10.1172/JCI36389
  35. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:1526-1533. https://doi.org/10.1056/NEJMoa021933
  36. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 2000;408:600-605. https://doi.org/10.1038/35046102
  37. Pang M, Martinez AF, Jacobs J, Balkan W, Troen BR. RANK ligand and interferon gamma differentially regulate cathepsin gene expression in pre-osteoclastic cells. Biochem Biophys Res Commun 2005;328:756-763. https://doi.org/10.1016/j.bbrc.2004.12.005
  38. Abu-Amer Y. IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-κB. J Clin Invest 2001;107:1375-1385.  https://doi.org/10.1172/JCI10530
  39. Bendixen AC, Shevde NK, Dienger KM, Willson TM, Funk CD, Pike JW. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor γ1. Proc Natl Acad Sci U S A 2001;98:2443-2448. https://doi.org/10.1073/pnas.041493198
  40. Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am J Pathol 2015;185:3011-3024. https://doi.org/10.1016/j.ajpath.2015.07.017
  41. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999;103:1345-1352. https://doi.org/10.1172/JCI5703
  42. Zwerina K, Koenders M, Hueber A, Marijnissen RJ, Baum W, Heiland GR, Zaiss M, McLnnes I, Joosten L, van den Berg W, et al. Anti IL-17A therapy inhibits bone loss in TNF-α-mediated murine arthritis by modulation of the T-cell balance. Eur J Immunol 2012;42:413-423. https://doi.org/10.1002/eji.201141871
  43. Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, Schulze-Koops H, Horwood N, Cope A, Schett G. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum 2007;56:4104-4112. https://doi.org/10.1002/art.23138
  44. Zaiss MM, Sarter K, Hess A, Engelke K, Bohm C, Nimmerjahn F, Voll R, Schett G, David JP. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum 2010;62:2328-2338. https://doi.org/10.1002/art.27535
  45. Axmann R, Herman S, Zaiss M, Franz S, Polzer K, Zwerina J, Herrmann M, Smolen J, Schett G. CTLA-4 directly inhibits osteoclast formation. Ann Rheum Dis 2008;67:1603-1609. https://doi.org/10.1136/ard.2007.080713
  46. van Venrooij WJ, Pruijn GJ. Citrullination: a small change for a protein with great consequences for rheumatoid arthritis. Arthritis Res 2000;2:249-251. https://doi.org/10.1186/ar95
  47. Stenberg P, Roth B, Wollheim FA. Peptidylarginine deiminases and the pathogenesis of rheumatoid arthritis: a reflection of the involvement of transglutaminase in coeliac disease. Eur J Intern Med 2009;20:749-755. https://doi.org/10.1016/j.ejim.2009.08.007
  48. James EA, Moustakas AK, Berger D, Huston L, Papadopoulos GK, Kwok WW. Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling. Mol Immunol 2008;45:2651-2659. https://doi.org/10.1016/j.molimm.2007.12.013
  49. Koning F, Thomas R, Rossjohn J, Toes RE. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat Rev Rheumatol 2015;11:450-461. https://doi.org/10.1038/nrrheum.2015.59
  50. Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med 2013;210:2569-2582. https://doi.org/10.1084/jem.20131241
  51. Catrina AI, Ytterberg AJ, Reynisdottir G, Malmstrom V, Klareskog L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol 2014;10:645-653. https://doi.org/10.1038/nrrheum.2014.115
  52. Holers VM, Demoruelle MK, Kuhn KA, Buckner JH, Robinson WH, Okamoto Y, Norris JM, Deane KD. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol 2018;14:542-557. https://doi.org/10.1038/s41584-018-0070-0
  53. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018;4:18001.
  54. Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 2012;122:1791-1802.  https://doi.org/10.1172/JCI60975
  55. Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, Ytterberg AJ, Engstrom M, Fernandes-Cerqueira C, Amara K, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 2016;75:721-729. https://doi.org/10.1136/annrheumdis-2015-208093
  56. Kleyer A, Finzel S, Rech J, Manger B, Krieter M, Faustini F, Araujo E, Hueber AJ, Harre U, Engelke K, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 2014;73:854-860. https://doi.org/10.1136/annrheumdis-2012-202958
  57. Faloni AP, Sasso-Cerri E, Rocha FR, Katchburian E, Cerri PS. Structural and functional changes in the alveolar bone osteoclasts of estrogen-treated rats. J Anat 2012;220:77-85. https://doi.org/10.1111/j.1469-7580.2011.01449.x
  58. Wigerblad G, Bas DB, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar KS, Rogoz K, Kato J, Sandor K, Su J, Jimenez-Andrade JM, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis 2016;75:730-738. https://doi.org/10.1136/annrheumdis-2015-208094
  59. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol 2012;198:773-783. https://doi.org/10.1083/jcb.201203170
  60. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 2013;5:178ra40.
  61. So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol 2017;13:639-647. https://doi.org/10.1038/nrrheum.2017.155
  62. Major TJ, Dalbeth N, Stahl EA, Merriman TR. An update on the genetics of hyperuricaemia and gout. Nat Rev Rheumatol 2018;14:341-353. https://doi.org/10.1038/s41584-018-0004-x
  63. Choe JY, Park KY, Kim SK. Monosodium urate in the presence of RANKL promotes osteoclast formation through activation of c-Jun N-terminal kinase. Mediators Inflamm 2015;2015:597512.
  64. Wang C, Qu C, Alippe Y, Bonar SL, Civitelli R, Abu-Amer Y, Hottiger MO, Mbalaviele G. Poly-ADP-ribosylation-mediated degradation of ARTD1 by the NLRP3 inflammasome is a prerequisite for osteoclast maturation. Cell Death Dis 2016;7:e2153.
  65. Robaszkiewicz A, Qu C, Wisnik E, Ploszaj T, Mirsaidi A, Kunze FA, Richards PJ, Cinelli P, Mbalaviele G, Hottiger MO. ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-κB-dependent transcription of IL-1β. Sci Rep 2016;6:21131.
  66. Qu C, Bonar SL, Hickman-Brecks CL, Abu-Amer S, McGeough MD, Pena CA, Broderick L, Yang C, Grimston SK, Kading J, et al. NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J 2015;29:1269-1279. https://doi.org/10.1096/fj.14-264804
  67. Takami M, Kim N, Rho J, Choi Y. Stimulation by Toll-like receptors inhibits osteoclast differentiation. J Immunol 2002;169:1516-1523. https://doi.org/10.4049/jimmunol.169.3.1516
  68. Ji JD, Park-Min KH, Shen Z, Fajardo RJ, Goldring SR, McHugh KP, Ivashkiv LB. Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-γ in human osteoclast precursors. J Immunol 2009;183:7223-7233. https://doi.org/10.4049/jimmunol.0900072
  69. Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 2005;52:2936-2946. https://doi.org/10.1002/art.21238
  70. Rezaei H, Saevarsdottir S, Forslind K, Albertsson K, Wallin H, Bratt J, Ernestam S, Geborek P, Pettersson IF, van Vollenhoven RF. In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial. Ann Rheum Dis 2012;71:186-191. https://doi.org/10.1136/annrheumdis-2011-200038
  71. Takeuchi T, Tanaka Y, Ishiguro N, Yamanaka H, Yoneda T, Ohira T, Okubo N, Genant HK, van der Heijde D. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis 2016;75:983-990. https://doi.org/10.1136/annrheumdis-2015-208052
  72. Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 2012;11:234-250. https://doi.org/10.1038/nrd3669