Abstract
The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.
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References
McInnes IB, Schett G (2017) Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 389:2328–2337. https://doi.org/10.1016/S0140-6736(17)31472-1
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388:2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8
Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF (2013) How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat Med 19:822–824. https://doi.org/10.1038/nm.3260
Redlich K, Smolen JS (2012) Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 11:234–250. https://doi.org/10.1038/nrd3669
McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219. https://doi.org/10.1056/NEJMra1004965
Baron R, Gori F (2018) Targeting WNT signaling in the treatment of osteoporosis. Curr Opin Pharmacol 40:134–141. https://doi.org/10.1016/j.coph.2018.04.011
Eastell R, Szulc P (2017) Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol 5:908–923. https://doi.org/10.1016/S2213-8587(17)30184-5
Eastell R, O’Neill TW, Hofbauer LC, Langdahl B, Reid IR, Gold DT, Cummings SR (2016) Postmenopausal osteoporosis. Nat Rev Dis Primers 2:16069. https://doi.org/10.1038/nrdp.2016.69
Black DM, Rosen CJ (2016) Clinical practice. Postmenopausal osteoporosis. N Engl J Med 374:254–262. https://doi.org/10.1056/NEJMcp1513724
Hendrickx G, Boudin E, Van Hul W (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11:462–474. https://doi.org/10.1038/nrrheum.2015.48
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192. https://doi.org/10.1038/nm.3074
Tanaka Y, Morimoto I, Nakano Y, Okada Y, Hirota S, Nomura S, Nakamura T, Eto S (1995) Osteoblasts are regulated by the cellular adhesion through ICAM-1 and VCAM-1. J Bone Miner Res 10:1462–1469
Terashima A, Takayanagi H (2018) Overview of osteoimmunology. Calcif Tissue Int 102:503–511. https://doi.org/10.1007/s00223-018-0417-1
Dubrovsky AM, Lim MJ, Lane NE (2018) Osteoporosis in rheumatic diseases: anti-rheumatic drugs and the skeleton. Calcif Tissue Int 102:607–618. https://doi.org/10.1007/s00223-018-0401-9
Catrina AI, Svensson CI, Malmström V, Schett G, Klareskog L (2017) Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol 13:79–86. https://doi.org/10.1038/nrrheum.2016.200
Malmström V, Catrina AI, Klareskog L (2017) The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol 17:60–75. https://doi.org/10.1038/nri.2016.124
Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H (2017) Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 97:1295–1349. https://doi.org/10.1152/physrev.00036.2016
Szentpétery Á, Horváth Á, Gulyás K, Pethö Z, Bhattoa HP, Szántó S, Szücs G, FitzGerald O, Schett G, Szekanecz Z (2017) Effects of targeted therapies on the bone in arthritides. Autoimmun Rev 16:313–320. https://doi.org/10.1016/j.autrev.2017.01.014
Khosla S (2013) Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci 68:1226–1235. https://doi.org/10.1093/gerona/gls163
Takayanagi H (2012) New developments in osteoimmunology. Nat Rev Rheumatol 8:684–689. https://doi.org/10.1038/nrrheum.2012.167
Tanaka Y, Nakayamada S, Okada Y (2005) Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 4:325–328
Tanaka Y, Maruo A, Fujii K, Nomi M, Nakamura T, Eto S, Minami Y (2000) ICAM-1 discriminates functionally different populations of human osteoblasts: characteristic involvement of cell cycle regulators. J Bone Miner Res 15:1912–1923
Horowitz MC, Bothwell AL, Hesslein DG, Pflugh DL, Schatz DG (2005) B cells and osteoblast and osteoclast development. Immunol Rev 208:141–153
Schett G, Saag KG, Bijlsma JW (2010) From bone biology to clinical outcome: state of the art and future perspectives. Ann Rheum Dis 69:1415–1419
Malemud CJ (2017) Matrix metalloproteinases and synovial joint pathology. Prog Mol Biol Transl Sci 148:305–325. https://doi.org/10.1016/bs.pmbts.2017.03.003
Herrak P, Görtz B, Hayer S, Redlich K, Reiter E, Gasser J, Bergmeister H, Kollias G, Smolen JS, Schett G (2004) Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis. Arthritis Rheum 50:2327–2337
Smolen JS, Breedveld FC, Burmester GR et al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75:3–15
Smolen JS, Landewé R, Bijlsma J et al (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. 2016 update. Ann Rheum Dis 76:960–978
Tanaka Y (2013) Next stage of RA treatment: TNF-inhibitor-free remission will be a possible treatment goal? Ann Rheum Dis 72:ii124–ii127
Catrina AI, Klint EAF, Ernestam S, Catrina SB, Makrygiannakis D, Botusan IR, Klareskog L, Ulfgren AK (2006) Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis. Arthritis Rheum 54:76–81
Tanaka Y, Ohira T (2018) Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. Curr Opin Pharmacol 40:110–111
Takeuchi T, Tanaka Y, Ishiguro N, Yamanaka H, Yoneda Y, Ohira T, Okuno N, Gennant HK, van der Heijde D (2016) 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, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis 75:983–990
Tanaka Y, Maeshima Y, Yamaoaka K (2012) In vitro and in vivo analysis of a Jak inhibitor in rheumatoid arthritis. Ann Rheum Dis 71:i70–i74
Maeshima K, Yamaoaka K, Kubo S, Nakano K, Iwata S, Saito K, Ohishi M, Miyahara H, Tanaka S, Ishi K, Yoshimatsu H, Tanaka Y (2012) A JAK inhibitor tofacitinib regulates synovitis through inhibition of IFN-g and IL-17 production by human CD4 + T cells. Arthritis Rheum 64:1790–1798
Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S, Tanaka Y (2014) The JAK inhibitor tofacitinib reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis 73:2192–2198
Wang S-P, Iwata S, Nakayamada S, Sakata K, Yamaoka K, Tanaka Y (2014) Tofacitinib, a Jak inhibitor, inhibits human B cell activation in vitro. Ann Rheum Dis 73:2213–2215
van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Wyman BT, Gruben D, Benda B, Wallenstein G, Krishnaswami S, Zwillich SH, Bradley JD, Connell CA, The ORAL Scan investigators (2013) Tofacitinib (CP-690,550) in patients with rheumatoid arthritis on methotrexate: 12 month data from a 24 month Phase 3 randomized radiographic study. Arthritis Rheum 65:559–570
Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, del Morales CL, Gonzaga JR, Yakushin S, Ishii T, Emoto K, Veatie S, Arora V, Rooney T, Schlichting D, Macias WL, de Bono S (2017) Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 376:652–662
Tanaka Y. The JAK inhibitors: Do they bring a paradigm shift for the management of rheumatic diseases? Rheumatology (in press)
Acknowledgements
The authors thank all medical staff in all institutions for providing the data. This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan, through UOEH Grant for Advanced Research.
Funding
This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Agency for Medical Research and Development, and the University of Occupational and Environmental Health (UOEH), Japan, through UOEH Grant for Advanced Research.
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Y. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei and has received research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama.
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Tanaka, Y. Clinical immunity in bone and joints. J Bone Miner Metab 37, 2–8 (2019). https://doi.org/10.1007/s00774-018-0965-5
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DOI: https://doi.org/10.1007/s00774-018-0965-5