Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of joint destruction in rheumatoid arthritis — immune cell–fibroblast–bone interactions

Abstract

Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.

Key points

  • T helper 17 (TH17) cells and autoantibodies promote inflammation and tissue destruction in rheumatoid arthritis (RA) by activating other immune cells and synovial fibroblasts, leading to synovitis, bone erosion and cartilage damage.

  • Synovial fibroblasts in RA comprise pro-inflammatory and tissue-destructive subsets, the latter of which express RANKL and matrix metalloproteinases that are involved in osteoclastic bone resorption and cartilage degradation, respectively.

  • Bone lesions in RA are classified as bone erosion, periarticular bone loss and systemic osteoporosis, which are induced by distinct mechanisms.

  • The integration of data from single-cell RNA sequencing and biological studies provides a detailed depiction of the interplay among immune cells, fibroblasts and bone in RA pathogenesis.

  • Therapeutic strategies to modulate pathogenic synovial fibroblasts and to achieve a balance between regulatory T cells and TH17 cells and/or between bone resorption and repair will help achieve structural remission.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanism of structural damage in rheumatoid arthritis.
Fig. 2: Immune cell–fibroblast–bone interplay in rheumatoid arthritis.

Similar content being viewed by others

References

  1. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Danks, L. et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann. Rheum. Dis. 75, 1187–1195 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Komatsu, N. & Takayanagi, H. Inflammation and bone destruction in arthritis: synergistic activity of immune and mesenchymal cells in joints. Front. Immunol. 3, 77 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Shim, J. H., Stavre, Z. & Gravallese, E. M. Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif. Tissue Int. 102, 533–546 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Okamoto, K. et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol. Rev. 97, 1295–1349 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Tsukasaki, M. et al. OPG production matters where it happened. Cell Rep. 32, 108124 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Robling, A. G. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283, 5866–5875 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Miyazaki, T. et al. Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity. Sci. Adv. 5, eaau7802 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Davidson, S. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat. Rev. Immunol. 21, 704–717 (2021).

    Article  PubMed  CAS  Google Scholar 

  17. Nygaard, G. & Firestein, G. S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16, 316–333 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pfeifle, R. et al. Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104–113 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Bondt, A. et al. ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. Ann. Rheum. Dis. 77, 1130–1136 (2018).

    CAS  PubMed  Google Scholar 

  22. Chang, M. H. et al. Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell Rep. 37, 109902 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cambre, I. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun. 9, 4613 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wu, X. et al. Single-cell sequencing of immune cells from anticitrullinated peptide antibody positive and negative rheumatoid arthritis. Nat. Commun. 12, 4977 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hua, S. & Dias, T. H. Hypoxia-inducible factor (HIF) as a target for novel therapies in rheumatoid arthritis. Front. Pharmacol. 7, 184 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Friscic, J. et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 54, 1002–1021 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei, K. et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 582, 259–264 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Armaka, M., Ospelt, C., Pasparakis, M. & Kollias, G. The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. Nat. Commun. 9, 618 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Nguyen, H. N. et al. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 46, 220–232 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bromley, M. & Woolley, D. E. Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum. 27, 968–975 (1984).

    Article  CAS  PubMed  Google Scholar 

  35. Takayanagi, H. et al. Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 43, 259–269 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Takayanagi, H. et al. A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis. Biochem. Biophys. Res. Commun. 240, 279–286 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Gravallese, E. M. et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 43, 250–258 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Pettit, A. R. et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am. J. Pathol. 159, 1689–1699 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Redlich, K. et al. Osteoclasts are essential for TNF-α-mediated joint destruction. J. Clin. Invest. 110, 1419–1427 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Meednu, N. et al. Production of RANKL by memory B cells: a link between B cells and bone erosion in rheumatoid arthritis. Arthritis Rheumatol. 68, 805–816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ota, Y. et al. Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis. Arthritis Res. Ther. 18, 67 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Komatsu, N. et al. Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis. J. Clin. Invest. 131, e143060 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  45. Herman, S. et al. Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum. 58, 3041–3050 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Lam, J. et al. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106, 1481–1488 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ochi, S. et al. Pathological role of osteoclast costimulation in arthritis-induced bone loss. Proc. Natl Acad. Sci. USA 104, 11394–11399 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Negishi-Koga, T. et al. Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 6, 6637 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Krishnamurthy, A. et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis. 75, 721–729 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Burska, A. N. et al. Receptor activator of nuclear factor κ-B ligand (RANKL) serum levels are associated with progression to seropositive/negative rheumatoid arthritis. Clin. Exp. Rheumatol. 39, 456–462 (2021).

    Article  PubMed  Google Scholar 

  52. Asano, T. et al. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat. Metab. 1, 868–875 (2019).

    Article  PubMed  Google Scholar 

  53. Sato, K. et al. TH17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Harre, U. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Ota, M. et al. Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases. Cell 184, 3006–3021 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Zaiss, M. M. et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum. 56, 4104–4112 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Komatsu, N. & Takayanagi, H. Regulatory T cells in arthritis. Prog. Mol. Biol. Transl. Sci. 136, 207–215 (2015).

    Article  PubMed  Google Scholar 

  62. Komatsu, N. et al. Pathogenic conversion of FOXP3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Kochi, Y. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat. Genet. 42, 515–519 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Walsh, N. C. et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J. Bone Miner. Res. 24, 1572–1585 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Gilbert, L. et al. Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2αA) is inhibited by tumor necrosis factor-α. J. Biol. Chem. 277, 2695–2701 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. de Rooy, D. P. et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann. Rheum. Dis. 72, 769–775 (2013).

    Article  PubMed  CAS  Google Scholar 

  67. Wehmeyer, C. et al. Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Sci. Transl. Med. 8, 330ra335 (2016).

    Article  CAS  Google Scholar 

  68. Matzelle, M. M. et al. Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation. Scand. J. Rheumatol. 45, 379–383 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Stashenko, P., Dewhirst, F. E., Rooney, M. L., Desjardins, L. A. & Heeley, J. D. Interleukin-1β is a potent inhibitor of bone formation in vitro. J. Bone Miner. Res. 2, 559–565 (1987).

    Article  CAS  PubMed  Google Scholar 

  70. Bellido, T., Borba, V. Z., Roberson, P. & Manolagas, S. C. Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. Endocrinology 138, 3666–3676 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. McGregor, N. E. et al. IL-6 exhibits both cis- and trans-signaling in osteocytes and osteoblasts, but only trans-signaling promotes bone formation and osteoclastogenesis. J. Biol. Chem. 294, 7850–7863 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gravallese, E. M. & Schett, G. Effects of the IL-23–IL-17 pathway on bone in spondyloarthritis. Nat. Rev. Rheumatol. 14, 631–640 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Kampylafka, E. et al. Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study. Arthritis Res. Ther. 20, 153 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4CD8 entheseal resident T cells. Nat. Med. 18, 1069–1076 (2016).

    Article  CAS  Google Scholar 

  75. Shaw, A. T., Maeda, Y. & Gravallese, E. M. IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res. Ther. 18, 104 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Ono, T. et al. IL-17-producing γδ T cells enhance bone regeneration. Nat. Commun. 7, 10928 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 17, 1473–1480 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Yoshida, Y. et al. Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production: pathogenic and therapeutic implications. Arthritis Rheumatol. 67, 1481–1490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Takagawa, S. et al. Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis. BMC Musculoskelet. Disord. 14, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. He, X. et al. Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis. EBioMedicine 41, 538–555 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goldring, S. R. Periarticular bone changes in rheumatoid arthritis: pathophysiological implications and clinical utility. Ann. Rheum. Dis. 68, 297–299 (2009).

    Article  PubMed  Google Scholar 

  83. Kleyer, A. et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann. Rheum. Dis. 73, 854–860 (2014).

    Article  PubMed  Google Scholar 

  84. Engdahl, C. et al. Periarticular bone loss in arthritis is induced by autoantibodies against citrullinated vimentin. J. Bone Miner. Res. 32, 1681–1691 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Lightman, S. M., Utley, A. & Lee, K. P. Survival of long-lived plasma cells (LLPC): piecing together the puzzle. Front. Immunol. 10, 965 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pioli, P. D. Plasma cells, the next generation: beyond antibody secretion. Front. Immunol. 10, 2768 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sun, W. et al. B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation. Nat. Commun. 9, 5127 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Courbon, G. et al. Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model. Sci. Rep. 8, 3492 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Werner, D. et al. Early changes of the cortical micro-channel system in the bare area of the joints of patients with rheumatoid arthritis. Arthritis Rheumatol. 69, 1580–1587 (2017).

    Article  PubMed  Google Scholar 

  90. Tanaka, Y. Managing osteoporosis and joint damage in patients with rheumatoid arthritis: an overview. J. Clin. Med. 10, 1241 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dubrovsky, A. M., Lim, M. J. & Lane, N. E. Osteoporosis in rheumatic diseases: anti-rheumatic drugs and the skeleton. Calcif. Tissue Int. 102, 607–618 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Haugeberg, G., Uhlig, T., Falch, J. A., Halse, J. I. & Kvien, T. K. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum. 43, 522–530 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, K. W., Kim, H. R., Kim, B. M., Cho, M. L. & Lee, S. H. TH17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am. J. Pathol. 185, 3011–3024 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Yellin, M. J. et al. Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation. J. Leukoc. Biol. 58, 209–216 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Van Seventer, G. A., Shimizu, Y., Horgan, K. J. & Shaw, S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J. Immunol. 144, 4579–4586 (1990).

    PubMed  Google Scholar 

  96. Damle, N. K. & Aruffo, A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 88, 6403–6407 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yamamura, Y. et al. Effector function of resting T cells: activation of synovial fibroblasts. J. Immunol. 166, 2270–2275 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Sawa, S. et al. Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J. Exp. Med. 203, 1459–1470 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sawai, H. et al. T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum. 52, 1392–1401 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Lee, J. H. et al. Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis. Arthritis Res. Ther. 19, 163 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Hirota, K. et al. Preferential recruitment of CCR6-expressing TH17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628–636 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Kikuchi, J. et al. Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response. Arthritis Res. Ther. 17, 10 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Hirota, K. et al. Autoimmune TH17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity 48, 1220–1232 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Park, Y. E. et al. IL-17 increases cadherin-11 expression in a model of autoimmune experimental arthritis and in rheumatoid arthritis. Immunol. Lett. 140, 97–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Tran, C. N. et al. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes. Arthritis Rheum. 56, 1497–1506 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Carmona-Rivera, C. et al. Synovial fibroblast–neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Burger, J. A., Zvaifler, N. J., Tsukada, N., Firestein, G. S. & Kipps, T. J. Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J. Clin. Invest. 107, 305–315 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bombardieri, M. et al. A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Ann. Rheum. Dis. 70, 1857–1865 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Orange, D. E. et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N. Engl. J. Med. 383, 218–228 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hasegawa, T. et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 20, 1631–1643 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Kuo, D. et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci. Transl. Med. 11, eaau8587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Diarra, D. et al. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 13, 156–163 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Brown, A. K. et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum. 58, 2958–2967 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Smolen, J. S. et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy study. Arthritis Rheum. 52, 1020–1030 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Roser-Page, S., Vikulina, T., Zayzafoon, M. & Weitzmann, M. N. CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model. Arthritis Rheumatol. 66, 990–999 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tyagi, A. M. et al. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity 49, 1116–1131 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bozec, A. et al. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci. Transl. Med. 6, 235ra60 (2014).

    Article  PubMed  CAS  Google Scholar 

  119. Zaiss, M. M. et al. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum. 62, 2328–2338 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Zaiss, M. M. et al. Regulatory T cells protect from local and systemic bone destruction in arthritis. J. Immunol. 184, 7238–7246 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Rauber, S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat. Med. 23, 938–944 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295–1306 (2020).

    Article  CAS  PubMed  Google Scholar 

  124. Cohen, S. B. et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 58, 1299–1309 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Takeuchi, T. et al. 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. 75, 983–990 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Takeuchi, T. et al. Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. Ann. Rheum. Dis. 78, 899–907 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Axmann, R. et al. CTLA-4 directly inhibits osteoclast formation. Ann. Rheum. Dis. 67, 1603–1609 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Blanco, F. J. et al. Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol. 69, 1144–1153 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Lubberts, E. et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 50, 650–659 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Glatt, S. et al. Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: a proof-of-concept study. Ann. Rheum. Dis. 78, 1033–1040 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Maeshima, K. et al. The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells. Arthritis Rheum. 64, 1790–1798 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Kubo, S. et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann. Rheum. Dis. 73, 2192–2198 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Combe, B. et al. Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial. Ann. Rheum. Dis. 80, 848–858 (2021).

    Article  CAS  PubMed  Google Scholar 

  134. Traves, P. G. et al. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Ann. Rheum. Dis. 80, 865–875 (2021).

    Article  CAS  PubMed  Google Scholar 

  135. Adam, S. et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci. Transl. Med. 12, eaay4447 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Murakami, K. et al. A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS ONE 12, e0181126 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Matzelle, M. M. et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum. 64, 1540–1550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chen, X. X. et al. Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann. Rheum. Dis. 72, 1732–1736 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Marenzana, M., Vugler, A., Moore, A. & Robinson, M. Effect of sclerostin-neutralising antibody on periarticular and systemic bone in a murine model of rheumatoid arthritis: a microCT study. Arthritis Res. Ther. 15, R125 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Teng, Y. et al. Adenovirus-mediated delivery of Sema3A alleviates rheumatoid arthritis in a serum-transfer induced mouse model. Oncotarget 8, 66270–66280 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Zhang, H. et al. NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB. J. Clin. Invest. 124, 3200–3214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Sawai, H., Park, Y. W., He, X., Goronzy, J. J. & Weyand, C. M. Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 56, 3215–3225 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Laragione, T., Brenner, M., Sherry, B. & Gulko, P. S. CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis. Arthritis Rheum. 63, 3274–3283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Nanki, T. et al. Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J. Immunol. 173, 7010–7016 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Hamilton, J. A., Cook, A. D. & Tak, P. P. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat. Rev. Drug Discov. 16, 53–70 (2016).

    Article  PubMed  CAS  Google Scholar 

  146. Tanaka, Y. et al. Efficacy and safety of E6011, an anti-fractalkine monoclonal antibody, in patients with active rheumatoid arthritis with inadequate response to methotrexate: results of a randomized, double-blind, placebo-controlled phase II study. Arthritis Rheumatol. 73, 587–595 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yellin, M. et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 64, 1730–1739 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04134728 (2022).

  149. Finch, R. et al. Results of a phase 2 study of RG6125, an anti-cadherin-11 monoclonal antibody in rheumatoid arthritis patients with an inadequate response to anti- TNFα therapy [abstract OP0224]. Ann. Rheum. Dis. 78, 189 (2019).

    Google Scholar 

  150. Dorst, D. N. et al. Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy. Rheumatology https://doi.org/10.1093/rheumatology/keab664 (2021).

    Article  PubMed  Google Scholar 

  151. Pap, T. & Korb-Pap, A. Cartilage damage in osteoarthritis and rheumatoid arthritis–two unequal siblings. Nat. Rev. Rheumatol. 11, 606–615 (2015).

    Article  PubMed  Google Scholar 

  152. Araki, Y. & Mimura, T. Matrix metalloproteinase gene activation resulting from disordred epigenetic mechanisms in rheumatoid arthritis. Int. J. Mol. Sci. 18, 905 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  153. Posthumus, M. D. et al. Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with early rheumatoid arthritis. Rheumatology 38, 1081–1087 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Chang, S. H. et al. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nat. Commun. 10, 1442 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Han, E. J. et al. GREM1 is a key regulator of synoviocyte hyperplasia and invasiveness. J. Rheumatol. 43, 474–485 (2016).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to all the laboratory members, especially K. Okamoto, M. Tsukasaki and R. Ling for thoughtful discussion.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Hiroshi Takayanagi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Rheumatology thanks M. Nakamura, J. Lorenzo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Komatsu, N., Takayanagi, H. Mechanisms of joint destruction in rheumatoid arthritis — immune cell–fibroblast–bone interactions. Nat Rev Rheumatol 18, 415–429 (2022). https://doi.org/10.1038/s41584-022-00793-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-022-00793-5

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing