J Rheum Dis.  2016 Jun;23(3):148-153. 10.4078/jrd.2016.23.3.148.

Pro-inflammatory Cytokines Modulating Osteoclast Differentiation and Function

  • 1Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea. nacksung@jnu.ac.kr
  • 2Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Korea.


In general, bone homeostasis is maintained through the balance between bone formation and resorption. Disruption in this balance results in bone-related diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Often, enhanced osteoclastogenesis is followed by accelerated bone resorption that is induced by pro-inflammatory cytokines in osteoporosis or rheumatoid arthritis, and leads to bone destruction. In this review study, factors involved in osteoclast differentiation and function are discussed, and how the prevention of such factors is effective in ameliorating bone loss in osteoporosis or rheumatoid arthritis.


Bone and bones; Osteoclasts; Rheumatoid arthritis; Cytokines

MeSH Terms

Arthritis, Rheumatoid
Bone and Bones
Bone Resorption


  • Figure 1. Roles of proinflammatory cytokines in osteoclastogenesis. Pro-inflammatory cytokines are produced from various immune cells including T cells, B cells, macrophages, dendritic cells, FLS, etc. Proinflammatory cytokines induce osteoclastogenesis either dependent or independent of the RANKL-RANK signaling pathway. FLS: fibroblast-like synoviocytes, IL: interleukin, RANKL: receptor activator of nuclear factor kappa-B ligand, TNF-α: tumor necrosis factor alpha.


1. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010; 285:25103–8.
2. Charles JF, Aliprantis AO. Osteoclasts: more than ‘bone eaters’. Trends Mol Med. 2014; 20:449–59.
3. Imai Y, Youn MY, Inoue K, Takada I, Kouzmenko A, Kato S. Nuclear receptors in bone physiology and diseases. Physiol Rev. 2013; 93:481–523.
4. Soysa NS, Alles N, Aoki K, Ohya K. Osteoclast formation and differentiation: an overview. J Med Dent Sci. 2012; 59:65–74.
5. Chen YC, Sosnoski DM, Mastro AM. Breast cancer metastasis to the bone: mechanisms of bone loss. Breast Cancer Res. 2010; 12:215.
6. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001; 344:907–16.
7. Jung SM, Kim KW, Yang CW, Park SH, Ju JH. Cytokinemediated bone destruction in rheumatoid arthritis. J Immunol Res. 2014; 2014; 263625.
8. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012; 8:656–64.
9. Amarasekara DS, Yu J, Rho J. Bone loss triggered by the cytokine network in inflammatory autoimmune diseases. J Immunol Res. 2015; 2015; 832127.
10. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002; 2:364–71.
11. Mateen S, Zafar A, Moin S, Khan AQ, Zubair S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016; 455:161–71.
12. Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arthritis Res Ther. 2007; 9:203.
13. Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL. M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest. 2005; 115:3418–27.
14. Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001; 276:563–8.
15. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000; 191:275–86.
16. Gilbert L, He X, Farmer P, Rubin J, Drissi H, van Wijnen AJ, et al. Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2alpha A) is inhibited by tumor necrosis factor-alpha. J Biol Chem. 2002; 277:2695–701.
17. Heiland GR, Zwerina K, Baum W, Kireva T, Distler JH, Grisanti M, et al. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis. 2010; 69:2152–9.
18. Kim JH, Jin HM, Kim K, Song I, Youn BU, Matsuo K, et al. The mechanism of osteoclast differentiation induced by IL-1. J Immunol. 2009; 183:1862–70.
19. Kurz K, Herold M, Russe E, Klotz W, Weiss G, Fuchs D. Effects of antitumor necrosis factor therapy on osteoprotegerin, neopterin, and sRANKL concentrations in patients with Rheumatoid arthritis. Dis Markers. 2015; 2015; 276969.
20. Shealy DJ, Wooley PH, Emmell E, Volk A, Rosenberg A, Treacy G, et al. Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res. 2002; 4:R7.
21. Kawai VK, Stein CM, Perrien DS, Griffin MR. Effects of antitumor necrosis factor α agents on bone. Curr Opin Rheumatol. 2012; 24:576–85.
22. Ruscitti P, Cipriani P, Carubbi F, Liakouli V, Zazzeroni F, Di Benedetto P, et al. The role of IL-1β in the bone loss during rheumatic diseases. Mediators Inflamm. 2015; 2015; 782382.
23. Lacativa PG, Farias ML. Osteoporosis and inflammation. Arq Bras Endocrinol Metabol. 2010; 54:123–32.
24. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 2005; 115:282–90.
25. Jules J, Zhang P, Ashley JW, Wei S, Shi Z, Liu J, et al. Molecular basis of requirement of receptor activator of nuclear factor κ B signaling for interleukin 1-mediated osteoclastogenesis. J Biol Chem. 2012; 287:15728–38.
26. Lee YM, Fujikado N, Manaka H, Yasuda H, Iwakura Y. IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol. 2010; 22:805–16.
27. van den Berg WB, Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-I. Baillieres Best Pract Res Clin Rheumatol. 1999; 13:577–97.
28. Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol. 1999; 163:5049–55.
29. Srirangan S, Choy EH. The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010; 2:247–56.
30. Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol. 2002; 169:3353–62.
31. Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 2006; 54:158–68.
32. Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S. Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem. 2008; 283:11535–40.
33. Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, et al. IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol. 2011; 23:701–12.
34. De Benedetti F, Rucci N, Del Fattore A, Peruzzi B, Paro R, Longo M, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006; 54:3551–63.
35. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, et al. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994; 13:1189–96.
36. Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum. 2003; 48:1177–89.
37. Karmakar S, Kay J, Gravallese EM. Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention. Rheum Dis Clin North Am. 2010; 36:385–404.
38. Jin W, Dong C. IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect. 2013; 2:e60.
39. Adamopoulos IE, Bowman EP. Immune regulation of bone loss by Th17 cells. Arthritis Res Ther. 2008; 10:225.
40. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003; 14:155–74.
41. Adamopoulos IE, Chao CC, Geissler R, Laface D, Blumenschein W, Iwakura Y, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther. 2010; 12:R29.
42. Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol. 2003; 170:2655–62.
43. Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010; 129:311–21.
44. Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine. 2008; 41:92–104.
45. Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, 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. 2004; 50:650–9.
46. Genovese MC, Greenwald M, Cho CS, Berman A, Jin L, Cameron GS, et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal anti-body, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2014; 66:1693–704.
47. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010; 2:52ra72.
48. Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol. 2015; 11:562.
49. Adamopoulos IE, Tessmer M, Chao CC, Adda S, Gorman D, Petro M, et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J Immunol. 2011; 187:951–9.
50. Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by upregulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Eur J Immunol. 2008; 38:2845–54.
51. Yago T, Nanke Y, Kawamoto M, Furuya T, Kobashigawa T, Kamatani N, 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. 2007; 9:R96.
52. Dai SM, Shan ZZ, Xu H, Nishioka K. Cellular targets of in-terleukin-18 in rheumatoid arthritis. Ann Rheum Dis. 2007; 66:1411–8.
53. Dai SM, Nishioka K, Yudoh K. Interleukin (IL) 18 stimulates osteoclast formation through synovial T cells in rheumatoid arthritis: comparison with IL1 beta and tumour necrosis factor alpha. Ann Rheum Dis. 2004; 63:1379–86.
Full Text Links
  • JRD
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2023 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr