Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis
Seung-Ki Kwok
Catholic University of Korea, Seoul, South Korea
Drs. Kwok and Cho contributed equally to this work.
Search for more papers by this authorMi-La Cho
Catholic University of Korea, Seoul, South Korea
Drs. Kwok and Cho contributed equally to this work.
Search for more papers by this authorSeon-Yeong Lee
Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Sung-Hwan Park
Catholic University of Korea, Seoul, South Korea
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul St. Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South KoreaSearch for more papers by this authorSeung-Ki Kwok
Catholic University of Korea, Seoul, South Korea
Drs. Kwok and Cho contributed equally to this work.
Search for more papers by this authorMi-La Cho
Catholic University of Korea, Seoul, South Korea
Drs. Kwok and Cho contributed equally to this work.
Search for more papers by this authorSeon-Yeong Lee
Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Sung-Hwan Park
Catholic University of Korea, Seoul, South Korea
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul St. Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South KoreaSearch for more papers by this authorAbstract
Objective
Bone destruction is a critical pathology involved in the functional disability caused by rheumatoid arthritis (RA). Osteoclasts, which are specialized bone-resorbing cells regulated by cytokines such as RANKL, are implicated in bone destruction in RA. The aim of this study was to determine whether interleukin-21 (IL-21), a potent immunomodulatory 4–α-helical bundle type 1 cytokine, has osteoclastogenic activity in patients with RA and in mice with collagen-induced arthritis (CIA).
Methods
The expression of IL-21 in synovial tissue was examined using immunohistochemistry. The concentrations of IL-21 in serum and synovial fluid were determined by enzyme-linked immunosorbent assay. The levels of RANKL and osteoclastogenic markers were measured using real-time polymerase chain reaction. CD14+ monocytes from patients with RA or mouse bone marrow cells were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA or CD4+ T cells from mice with CIA in the presence of IL-21 and subsequently stained for tartrate-resistant acid phosphatase activity to determine osteoclast formation.
Results
IL-21 was up-regulated in the synovium, synovial fluid, and serum of patients with RA and in the synovium and serum of mice with CIA. IL-21 induced RANKL expression in mixed joint cells and CD4+ T cells from mice with CIA and in CD4+ T cells and FLS from patients with RA. Moreover, IL-21 enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in CD4+ T cells and FLS.
Conclusion
Our data suggest that IL-21 promotes osteoclastogenesis in RA. We believe that therapeutic strategies targeting IL-21 might be effective for the treatment of patients with RA, especially in preventing bone destruction.
REFERENCES
- 1 Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996; 85: 307–10.
- 2 Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis: passive responders or transformed aggressors? Arthritis Rheum 1996; 39: 1781–90.
- 3 Reece RJ, Canete JD, Parsons WJ, Emery P, Veale DJ. Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum 1999; 42: 1481–4.
- 4 Koch AE. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis 2003; 62 Suppl 2: ii60–7.
- 5 Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M, Dijkmans BA. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum 2004; 50: 36–42.
- 6 Gravallese EM. Bone destruction in arthritis. Ann Rheum Dis 2002; 61 Suppl 2: ii84–6.
- 7 O'Gradaigh D, Ireland D, Bord S, Compston JE. Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor α, interleukin 1, and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclasts. Ann Rheum Dis 2004; 63: 354–9.
- 8 Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: interactions of the bone and immune system. Endocr Rev 2008; 29: 403–40.
- 9 Lee SH, Kim TS, Choi Y, Lorenzo J. Osteoimmunology: cytokines and the skeletal system. BMB Rep 2008; 41: 495–510.
- 10 Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 2008; 26: 57–79.
- 11 Wei L, Laurence A, Elias KM, O'Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007; 282: 34605–10.
- 12 Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007; 448: 480–3.
- 13 Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006; 203: 2673–82.
- 14 Lundy SK, Sarkar S, Tesmer LA, Fox DA. Cells of the synovium in rheumatoid arthritis: T lymphocytes. Arthritis Res Ther 2007; 9: 202.
- 15 Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev 2008; 223: 87–113.
- 16 Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315–23.
- 17 Ju JH, Cho ML, Moon YM, Oh HJ, Park JS, Jhun JY, 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 2008; 181: 1507–18.
- 18 Cho ML, Kim WU, Min SY, Min DJ, Min JK, Lee SH, et al. Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor α production by rheumatoid synoviocytes. Arthritis Rheum 2002; 46: 42–51.
- 19 Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001; 44: 1003–12.
- 20 Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, et al. Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000; 43: 259–69.
- 21 Kim KW, Cho ML, Lee SH, Oh HJ, Kang CM, Ju JH, et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol Lett 2007; 110: 54–64.
- 22 Jungel A, Distler JH, Kurowska-Stolarska M, Seemayer CA, Seibl R, Forster A, et al. Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis. Arthritis Rheum 2004; 50: 1468–76.
- 23 Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2002; 298: 1630–4.
- 24 Ettinger R, Kuchen S, Lipsky PE. Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis 2008; 67 Suppl 3: iii83–6.
- 25 Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 2007: 353–63.
- 26 Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol 2007; 178: 3822–30.
- 27 Bubier JA, Bennett SM, Sproule TJ, Lyons BL, Olland S, Young DA, et al. Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus. Ann N Y Acad Sci 2007; 1110: 590–601.
- 28 Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer DJ, Morse HC 3rd, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A 2009; 106: 1518–23.
- 29 Li J, Shen W, Kong K, Liu Z. Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumatoid arthritis. Scand J Immunol 2006; 64: 515–22.
- 30 Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007; 56: 1152–63.
- 31 Jang E, Cho SH, Park H, Paik DJ, Kim JM, Youn J. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol 2009; 182: 4649–56.
- 32 Yuan SL, Jiang L, Zhang XL, Li SF, Duan HM, Wang XF. Serum IL-21 level in patients with primary Sjogren's syndrome and clinical significance of IL-21. Chinese J Cellular and Molecular Immunology 2007; 23: 124–6. In Chinese.
- 33 Duplomb L, Baud'huin M, Charrier C, Berreur M, Trichet V, Blanchard F, et al. Interleukin-6 inhibits receptor activator of nuclear factor κB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology 2008; 149: 3688–97.
- 34 Hulsmans HM, Jacobs JW, van der Heijde DM, van Albada-Kuipers GA, Schenk Y, Bijlsma JW. The course of radiologic damage during the first six years of rheumatoid arthritis. Arthritis Rheum 2000; 43: 1927–40.
- 35 Lindqvist E, Jonsson K, Saxne T, Eberhardt K. Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis. Ann Rheum Dis 2003; 62: 611–6.
- 36 Lindqvist E, Saxne T, Geborek P, Eberhardt K. Ten year outcome in a cohort of patients with early rheumatoid arthritis: health status, disease process, and damage. Ann Rheum Dis 2002; 61: 1055–9.
- 37 Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al, for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594–602.
- 38 Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675–81.
- 39 Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54: 26–37.
