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:

Effects of the IL-23–IL-17 pathway on bone in spondyloarthritis

Nature Reviews Rheumatology volume 14, pages 631–640 (2018)Cite this article

Subjects

Abstract

Over the past several years, a pathophysiological role for the IL-23–IL-17 pathway in human disease has been defined. A subset of rheumatic diseases, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are now acknowledged to be triggered by dysregulated IL-23–IL-17 pathway activation. Genetic evidence links the IL-23–IL-17 pathway to inflammation in these rheumatic diseases, and mechanistic data from mice support a functional role for IL-23–IL-17 pathway activation in the development of enthesitis and in entheseal bone formation. Furthermore, analysis of human tissue samples, as well as data from clinical trials, also supports a role for activation of the IL-23–IL-17 pathway in these diseases. The unique bone phenotype that occurs in PsA and AS is a surprising coexistence of both systemic bone loss and periosteal and entheseal bone formation and is likely to be the result of the actions of IL-23 and/or IL-17 on bone. However, the effects of these cytokines on bone cells are complex, and controversy remains regarding their exact roles in the specific bone microenvironments relevant to PsA and AS.

Key points

  • IL-23 is produced by activated myeloid cells, whereas IL-17 is predominantly produced by T cells and innate lymphoid cells.

  • Several lines of evidence support a role for the IL-23–IL-17 pathway in the pathogenesis of psoriatic arthritis (PsA) and ankylosing spondylitis (AS).

  • Bone changes that occur in PsA and AS include systemic bone loss, articular erosions and entheseal bone formation and reflect the combined effects of IL-23 and IL-17.

  • IL-17A promotes osteoclastogenesis directly, as well as indirectly, through the production or induction of receptor-activator of nuclear factor-κB ligand (RANKL) expression, whereas the effects of IL-23 on osteoclasts are pleotropic.

  • IL-17A exhibits differential effects on the maturation of osteoblast precursor cells to osteoblasts depending upon the stage of differentiation of the cellular precursor.

  • IL-17A blockade inhibits articular bone erosion and might also retard systemic bone loss in PsA and AS and enthesophyte formation in PsA.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Effects of IL-23 and IL-17 on bone.
Fig. 2: Effects of IL-23 and IL-17 on osteoclasts and osteoblasts.
Fig. 3: Essential characteristics of IL-17-dependent forms of arthritis.

Similar content being viewed by others

References

  1. Song, X., He, X., Li, X. & Qian, Y. The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell. Mol. Immunol. 13, 418–431 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Boutet, M. A., Nerviani, A., Gallo Afflitto, G. & Pitzalis, C. Role of the IL-23/IL-17 axis in psoriasis and psoriatic arthritis: the clinical importance of its divergence in skin and joints. Int. J. Mol. Sci. 19, e530 (2018).

    PubMed  Google Scholar 

  3. Ranganathan, V., Gracey, E., Brown, M. A., Inman, R. D. & Haroon, N. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat. Rev. Rheumatol. 13, 359–367 (2017).

    CAS  PubMed  Google Scholar 

  4. Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    CAS  PubMed  Google Scholar 

  6. Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  Google Scholar 

  7. Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ghoreschi, K. et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Montaldo, E., Juelke, K. & Romagnani, C. Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice. Eur. J. Immunol. 45, 2127–2182 (2015).

    Google Scholar 

  10. Keijsers, R. R., Joosten, I., van Erp, P. E., Koenen, H. J. & van de Kerkhof, P. C. Cellular sources of IL-17 in psoriasis: a paradigm shift? Exp. Dermatol. 23, 799–803 (2014).

    CAS  PubMed  Google Scholar 

  11. Razawy, W., van Driel, M. & Lubberts, E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur. J. Immunol. 48, 220–229 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Huffmeier, U. et al. Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J. Invest. Dermatol. 129, 355–358 (2009).

    PubMed  Google Scholar 

  13. Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    Google Scholar 

  14. Farh, K. K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

    CAS  Google Scholar 

  15. Uddin, M. et al. Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways. Sci. Rep. 5, 10314 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    CAS  PubMed  Google Scholar 

  17. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    PubMed  PubMed Central  Google Scholar 

  18. van Duivenvoorde, L. M. et al. Relationship between inflammation, bone destruction, and osteoproliferation in the HLA-B27/human β2 -microglobulin-transgenic rat model of spondylarthritis. Arthritis Rheum. 64, 3210–3219 (2012).

    PubMed  PubMed Central  Google Scholar 

  19. Aschermann, S. et al. Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway. Joint Bone Spine 83, 43–46 (2016).

    CAS  PubMed  Google Scholar 

  20. Appel, H. et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 60, 3257–3262 (2009).

    PubMed  Google Scholar 

  21. Neerinckx, B., Kollnberger, S., Shaw, J. & Lories, R. No evidence for a direct role of HLA-B27 in pathological bone formation in axial SpA. RMD Open 3, e000451 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

    CAS  PubMed  Google Scholar 

  23. Utriainen, L. et al. Expression of HLA-B27 causes loss of migratory dendritic cells in a rat model of spondyloarthritis. Arthritis Rheum. 64, 3199–3209 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ebihara, S., Date, F., Dong, Y. & Ono, M. Interleukin-17 is a critical target for the treatment of ankylosing enthesitis and psoriasis-like dermatitis in mice. Autoimmunity 48, 259–266 (2015).

    CAS  PubMed  Google Scholar 

  25. Abe, Y. et al. Ankylosing enthesitis associated with up-regulated IFN-γ and IL-17 production in (BXSB×NZB) F(1) male mice: a new mouse model. Mod. Rheumatol. 19, 316–322 (2009).

    CAS  PubMed  Google Scholar 

  26. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    CAS  PubMed  Google Scholar 

  27. Zhang, L. et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS ONE 7, e31000 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kenna, T. J. et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 64, 1420–1429 (2012).

    CAS  PubMed  Google Scholar 

  29. Mei, Y. et al. Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis. Clin. Rheumatol. 30, 269–273 (2011).

    PubMed  Google Scholar 

  30. Celis, R. et al. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res. Ther. 14, R93 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Appel, H. et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res. Ther. 13, R95 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cuthbert, R. J. et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 69, 1816–1822 (2017).

    CAS  PubMed  Google Scholar 

  33. Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    CAS  PubMed  Google Scholar 

  34. Mease, P. J. et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N. Engl. J. Med. 373, 1329–1339 (2015).

    CAS  PubMed  Google Scholar 

  35. Mease, P. J. et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann. Rheum. Dis. 76, 79–87 (2017).

    CAS  PubMed  Google Scholar 

  36. Ritchlin, C. et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann. Rheum. Dis. 73, 990–999 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. McInnes, I. B. et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382, 780–789 (2013).

    CAS  Google Scholar 

  38. Araujo, E. G. et al. Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study. Semin. Arthritis Rheum. https://doi.org/10.1016/j.semarthrit.2018.05.011 (2018).

  39. Baeten, D. et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann. Rheum. Dis. 77, 1295–1302 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. Poddubnyy, D., Hermann, K. G., Callhoff, J., Listing, J. & Sieper, J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann. Rheum. Dis. 73, 817–823 (2014).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. Kocijan, R. et al. Quantitative and qualitative changes of bone in psoriasis and psoriatic arthritis patients. J. Bone Miner. Res. 30, 1775–1783 (2015).

    PubMed  Google Scholar 

  43. Devogelaer, J. P., Maldague, B., Malghem, J. & Nagant de Deuxchaisnes, C. Appendicular and vertebral bone mass in ankylosing spondylitis. A comparison of plain radiographs with single- and dual-photon absorptiometry and with quantitative computed tomography. Arthritis Rheum. 35, 1062–1067 (1992).

    CAS  PubMed  Google Scholar 

  44. Donnelly, S. et al. Bone mineral density and vertebral compression fracture rates in ankylosing spondylitis. Ann. Rheum. Dis. 53, 117–121 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ogdie, A. et al. The risk of fracture among patients with psoriatic arthritis and psoriasis: a population-based study. Ann. Rheum. Dis. 76, 882–885 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    PubMed  Google Scholar 

  48. Neerinckx, B. & Lories, R. Mechanisms, impact and prevention of pathological bone regeneration in spondyloarthritis. Curr. Opin. Rheumatol. 29, 287–292 (2017).

    PubMed  Google Scholar 

  49. Simon, D. et al. Analysis of periarticular bone changes in patients with cutaneous psoriasis without associated psoriatic arthritis. Ann. Rheum. Dis. 75, 660–666 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  51. Schett, G. et al. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch. Intern. Med. 166, 2495–2501 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  53. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    CAS  PubMed  Google Scholar 

  54. Schett, G. Review: immune cells and mediators of inflammatory arthritis. Autoimmunity 41, 224–229 (2008).

    CAS  PubMed  Google Scholar 

  55. Walsh, N. C. & Gravallese, E. M. Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr. Opin. Rheumatol. 16, 419–427 (2004).

    PubMed  Google Scholar 

  56. 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).

    CAS  PubMed  Google Scholar 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. Daiichi Sankyo Company. Daiichi Sankyo obtains approval for additional indication for PRALIA® subcutaneous injection 60 mg syringe. Daiichi-Sankyo https://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006655.html (2017).

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

    CAS  PubMed  Google Scholar 

  61. Saleh, H. et al. Interleukin-33, a target of parathyroid hormone and oncostatin M, increases osteoblastic matrix mineral deposition and inhibits osteoclast formation in vitro. Endocrinology 152, 1911–1922 (2011).

    CAS  PubMed  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. Lee, Y. The role of interleukin-17 in bone metabolism and inflammatory skeletal diseases. BMB Rep. 46, 479–483 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

    CAS  PubMed  Google Scholar 

  67. Pollinger, B. et al. Th17 cells, not IL-17+ γδT cells, drive arthritic bone destruction in mice and humans. J. Immunol. 186, 2602–2612 (2011).

    PubMed  Google Scholar 

  68. Yago, T. et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-α antibody: a novel mechanism of osteoclastogenesis by IL-17. J. Cell. Biochem. 108, 947–955 (2009).

    CAS  PubMed  Google Scholar 

  69. Adamopoulos, I. E. et al. Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors. Arthritis Res. Ther. 12, R29 (2010).

    PubMed  PubMed Central  Google Scholar 

  70. Katz, Y., Nadiv, O. & Beer, Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts: a possible role as a “fine-tuning cytokine” in inflammation processes. Arthritis Rheum. 44, 2176–2184 (2001).

    CAS  PubMed  Google Scholar 

  71. Jovanovic, D. V. et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages. J. Immunol. 160, 3513–3521 (1998).

    CAS  PubMed  Google Scholar 

  72. van der Heijde, D. et al. Brief report: Secukinumab provides significant and sustained inhibition of joint structural damage in a phase III study of active psoriatic arthritis. Arthritis Rheumatol. 68, 1914–1921 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. Huang, H. et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 16, 1332–1343 (2009).

    CAS  PubMed  Google Scholar 

  74. Osta, B., Lavocat, F., Eljaafari, A. & Miossec, P. Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells. Front. Immunol. 5, 425 (2014).

    PubMed  PubMed Central  Google Scholar 

  75. Goswami, J., Hernandez-Santos, N., Zuniga, L. A. & Gaffen, S. L. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur. J. Immunol. 39, 2831–2839 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. DeSelm, C. J. et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J. Cell. Biochem. 113, 2895–2902 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Uluckan, O. et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci. Transl Med. 8, 330ra37 (2016).

    PubMed  Google Scholar 

  78. 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, 104–113 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Kim, Y. G. et al. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Arch. Oral Biol. 59, 897–905 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Nam, D. et al. T-Lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair. PLoS ONE 7, e40044 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Croes, M. et al. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone 84, 262–270 (2016).

    CAS  PubMed  Google Scholar 

  83. Yago, T. et al. IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res. Ther. 9, R96 (2007).

    PubMed  PubMed Central  Google Scholar 

  84. Ju, J. H. et al. IL-23 induces receptor activator of NF-κB ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model. J. Immunol. 181, 1507–1518 (2008).

    CAS  PubMed  Google Scholar 

  85. Li, X. et al. IL-23 induces receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-κB signal pathways. Immunol. Lett. 127, 100–107 (2010).

    CAS  PubMed  Google Scholar 

  86. Chen, L., Wei, X. Q., Evans, B., Jiang, W. & Aeschlimann, D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-κB (RANK) expression in myeloid precursor cells. Eur. J. Immunol. 38, 2845–2854 (2008).

    CAS  PubMed  Google Scholar 

  87. Shin, H. S. et al. Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis. J. Immunol. 194, 316–324 (2015).

    CAS  PubMed  Google Scholar 

  88. Kamiya, S. et al. Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation. J. Bone Miner. Metab. 25, 277–285 (2007).

    CAS  PubMed  Google Scholar 

  89. Quinn, J. M. et al. IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. J. Immunol. 181, 5720–5729 (2008).

    CAS  PubMed  Google Scholar 

  90. Adamopoulos, I. E. et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J. Immunol. 187, 951–959 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kavanaugh, A. et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann. Rheum. Dis. 73, 1000–1006 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, J. R. et al. Different modulatory effects of IL-17, IL-22, and IL-23 on osteoblast differentiation. Mediators Inflamm. 2017, 5950395 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Reinhardt, A. & Prinz, I. Whodunit? The contribution of interleukin (IL)-17/IL-22- producing γδ T cells, αβ cells T cells, and innate lymphoid cells to the pathogenesis of spondyloarthritis. Front. Immunol. 9, 885 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. Karczewski, J., Dobrowolska, A., Rychlewska-Hanczewska, A. & Adamski, Z. New insights into the role of T cells in pathogenesis of psoriasis and psoriatic arthritis. Autoimmunity 49, 435–450 (2016).

    CAS  PubMed  Google Scholar 

  97. Mitra, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. Functional role of IL-22 in psoriatic arthritis. Arthritis Res. Ther. 14, R65 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Yang, L. et al. Augmented Th17 differentiation leads to cutaneous and synovio-entheseal inflammation in a novel model of psoriatic arthritis. Arthritis Rheumatol. 70, 855–867 (2018).

    CAS  PubMed  Google Scholar 

  99. Kim, K. W. et al. Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis Rheum. 64, 1015–1023 (2012).

    CAS  PubMed  Google Scholar 

  100. El-Zayadi, A. A. et al. Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology 56, 488–493 (2017).

    PubMed  Google Scholar 

  101. McGonagle, D., Lories, R. J., Tan, A. L. & Benjamin, M. The concept of a “synovio-entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum. 56, 2482–2491 (2007).

    PubMed  Google Scholar 

  102. Lisowska, B., Kosson, D. & Domaracka, K. Lights and shadows of NSAIDs in bone healing: the role of prostaglandins in bone metabolism. Drug Des. Devel. Ther. 12, 1753–1758 (2018).

    PubMed  PubMed Central  Google Scholar 

  103. Wang, Z. et al. The positive effects of secreting cytokines IL-17 and IFN-γ on the early-stage differentiation and negative effects on the calcification of primary osteoblasts in vitro. Int. Immunopharmacol. 57, 1–10 (2018).

    CAS  PubMed  Google Scholar 

  104. Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).

    CAS  PubMed  Google Scholar 

  105. Braun, J. et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann. Rheum. Dis. 76, 1070–1077 (2017).

    CAS  PubMed  Google Scholar 

  106. Landewe, R., Dougados, M., Mielants, H., van der Tempel, H. & van der Heijde, D. Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann. Rheum. Dis. 68, 863–867 (2009).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank S. Williams for editorial assistance. The work of E.M.G. was partially supported by the Timothy and Elaine Peterson Research Fund (UMMS; P60037138450000). The work of G.S. was partially supported by the German Research Council (DFG; CRC1181).

Reviewer information

Nature Reviews Rheumatology thanks A. Deodhar, E. Lubberts and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Ellen M. Gravallese

  2. Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany

    Georg Schett

Authors
  1. Ellen M. Gravallese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georg Schett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Ellen M. Gravallese.

Ethics declarations

Competing interests

E.M.G. declares that she has received research funding from AbbVie and Eli Lilly. G.S. declares no competing interests.

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

Gravallese, E.M., Schett, G. Effects of the IL-23–IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol 14, 631–640 (2018). https://doi.org/10.1038/s41584-018-0091-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-018-0091-8

This article is cited by

Search

Advanced 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