Review
Immune regulation of bone loss by Th17 cells in oestrogen-deficient osteoporosis
Renqing Zhao,
Corresponding Author
Renqing Zhao
College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
Correspondence to: Renqing Zhao, College of Physical Education and Health Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, Zhejiang Province 321004, China. Tel.: +86 579 82298809; fax: +86 579 82297990; e-mail: [email protected]Search for more papers by this authorRenqing Zhao,
Corresponding Author
Renqing Zhao
College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
Correspondence to: Renqing Zhao, College of Physical Education and Health Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, Zhejiang Province 321004, China. Tel.: +86 579 82298809; fax: +86 579 82297990; e-mail: [email protected]Search for more papers by this authorAbstract
Background
The role of T helper (Th) 17 cells in autoimmune diseases has been extensively studied recently, but its function in oestrogen-deficient osteoporosis remains undefined. This review aimed to explore the role of Th17 cells in regulating bone loss induced by oestrogen deficiency.
Materials and methods
We searched PubMed, Embase, Google Scholar and Biosis up to 1 February 2013 for immune regulation of oestrogen-deficient osteoporosis by Th17 cells. Terms relevant to immunity, oestrogen deficiency, osteoporosis and Th17 cells were used for database searching. Seventy-five papers met the predetermined searching criteria.
Results
Studies indicate Th17 lineage to be a potent osteoclastogenic mediator in oestrogen-deficient osteoporosis. Oestrogen deficiency promotes osteoclastogenesis by up-regulating Th17 cell populations in bone marrow and IL-17 levels in peripheral blood. Meanwhile, transcription factors involved in Th17 cell differentiation, such as RORγt and RORα, are highly expressed in ovariectomized animals. Treatment with IL-17 significantly promotes production of RANKL, TNF and IL-6 as well as TRAP+ cells in culture; blocking IL-17 pathway significantly reduces abundance of Th17 cells and effectively prevents bone loss in ovariectomized mice.
Conclusions
The main body of literatures suggests Th17 to be a critical modulator in the pathogenesis of oestrogen-deficient osteoporosis, which supports the notion that oestrogen-deficient osteoporosis is a complex interplay between oestrogen, osteoclastogenic cytokines and osteoclasts. In addition, therapeutic strategies targeting IL-17 networks may be clinically useful in treatment for postmenopausal osteoporosis.
References
- 1Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2012; 51(Suppl. 5): v3–11.
- 2Okamoto K, Takayanagi H. Regulation of bone by the adaptive immune system in arthritis. Arthritis Res Ther 2011; 13: 219.
- 3Maruotti N, Grano M, Colucci S, d'Onofrio F, Cantatore FP. Osteoclastogenesis and arthritis. Clin Exp Med 2011; 11: 137–45.
- 4Takayanagi H, Juji T, Miyazaki T, Iizuka H, Takahashi T, Isshiki M et al. Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest 1999; 104: 137–46.
- 5Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402: 304–9.
- 6Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009; 5: 667–76.
- 7Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 1999; 265: 144–50.
- 8Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 1990; 33: 768–73.
- 9Mangashetti LS, Khapli SM, Wani MR. IL-4 inhibits bone-resorbing activity of mature osteoclasts by affecting NF-kappa B and Ca2+ signaling. J Immunol 2005; 175: 917–25.
- 10Sato 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.
- 11Wei S, Wang MW, Teitelbaum SL, Ross FP. Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-kappa B and mitogen-activated protein kinase signaling. J Biol Chem 2002; 277: 6622–30.
- 12Yamada A, Takami M, Kawawa T, Yasuhara R, Zhao B, Mochizuki A et al. Interleukin-4 inhibition of osteoclast differentiation is stronger than that of interleukin-13 and they are equivalent for induction of osteoprotegerin production from osteoblasts. Immunology 2007; 120: 573–9.
- 13Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 2000; 408: 600–5.
- 14Kotake S, Nanke Y, Mogi M, Kawamoto M, Furuya T, Yago T et al. IFN-gamma-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL. Eur J Immunol 2005; 35: 3353–63.
- 15Palmqvist P, Lundberg P, Persson E, Johansson A, Lundgren I, Lie A et al. Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway. J Biol Chem 2006; 281: 2414–29.
- 16Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221–42.
- 17Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte 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 2000; 13: 715–25.
- 18Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D. Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. FASEB J 2004; 18: 1318–20.
- 19Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003; 278: 1910–4.
- 20Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233–40.
- 21Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 2006; 177: 566–73.
- 22Hofstetter HH, Ibrahim SM, Koczan D, Kruse N, Weishaupt A, Toyka KV et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 2005; 237: 123–30.
- 23Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003; 171: 6173–7.
- 24Bush KA, Farmer KM, Walker JS, Kirkham BW. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum 2002; 46: 802–5.
- 25Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123–32.
- 26Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–41.
- 27Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–8.
- 28Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24: 179–89.
- 29McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007; 8: 1390–7.
- 30Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol 2007; 19: 409–17.
- 31McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity 2008; 28: 445–53.
- 32Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008; 28: 29–39.
- 33Moseley L. Unraveling the barriers to reconceptualization of the problem in chronic pain: the actual and perceived ability of patients and health professionals to understand the neurophysiology. J Pain 2003; 4: 184–9.
- 34Van bezooijen RL, Farih-Sips HC, Papapoulos SE, Lowik CW. Interleukin-17: a new bone acting cytokine in vitro. J Bone Miner Res 1999; 14: 1513–21.
- 35Zrioual S, Toh ML, Tournadre A, Zhou Y, Cazalis MA, Pachot A et al. IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood. J Immunol 2008; 180: 655–63.
- 36Shen F, Gaffen SL. Structure–function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 2008; 41: 92–104.
- 37Novatchkova M, Leibbrandt A, Werzowa J, Neubuser A, Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci 2003; 28: 226–9.
- 38Kawai T, Akira S. TLR signaling. Semin Immunol 2007; 19: 24–32.
- 39Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 2007; 8: 247–56.
- 40Chang SH, Park H, Dong C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem 2006; 281: 35603–7.
- 41Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007; 8: 942–9.
- 42Pene J, Chevalier S, Preisser L, Venereau E, Guilleux MH, Ghannam S et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008; 180: 7423–30.
- 43Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996; 11: 88–95.
- 44Romas E, Gillespie MT, Martin TJ. Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 2002; 30: 340–6.
- 45Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999; 103: 1345–52.
- 46Pacifici R. Role of T cells in ovariectomy induced bone loss–revisited. J Bone Miner Res 2012; 27: 231–9.
- 47Zhao R. Immune regulation of osteoclast function in postmenopausal osteoporosis: a critical interdisciplinary perspective. Int J Med Sci 2012; 9: 825–32.
- 48Rosen CJ. Pathogenesis of osteoporosis. Baillieres Best Pract Res Clin Endocrinol Metab 2000; 14: 181–93.
- 49Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257: 88–91.
- 50Jilka RL, Passeri G, Girasole G, Cooper S, Abrams J, Broxmeyer H et al. Estrogen loss upregulates hematopoiesis in the mouse: a mediating role of IL-6. Exp Hematol 1995; 23: 500–6.
- 51Bell K, Loveridge N, Lunt M, Lindsay PC, Reeve J. Oestrogen suppression increases Haversian resorption depth as well as remodelling activity in women with endometriosis. Bone 1996; 19: 131S.
10.1016/8756-3282(96)89265-9 Google Scholar
- 52Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001; 104: 719–30.
- 53Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T et al. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 2003; 111: 1651–64.
- 54Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci USA 2001; 98: 13960–5.
- 55Gao Y, Grassi F, Ryan MR, Terauchi M, Page K, Yang X et al. IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest 2007; 117: 122–32.
- 56Gao Y, Qian WP, Dark K, Toraldo G, Lin AS, Guldberg RE et al. Estrogen prevents bone loss through transforming growth factor beta signaling in T cells. Proc Natl Acad Sci USA 2004; 101: 16618–23.
- 57Grassi F, Tell G, Robbie-Ryan M, Gao Y, Terauchi M, Yang X et al. Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation. Proc Natl Acad Sci USA 2007; 104: 15087–92.
- 58Li JY, Tawfeek H, Bedi B, Yang X, Adams J, Gao KY et al. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci USA 2011; 108: 768–73.
- 59Robbie-Ryan M, Pacifici R, Weitzmann MN. IL-7 drives T cell-mediated bone loss following ovariectomy. Ann N Y Acad Sci 2006; 1068: 348–51.
- 60D'Amelio P, Grimaldi A, Di Bella S, Brianza SZ, Cristofaro MA, Tamone C et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone 2008; 43: 92–100.
- 61Rogers A, Eastell R. The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. Bone 2001; 29: 30–4.
- 62Pacifici R. T cells: critical bone regulators in health and disease. Bone 2010; 47: 461–71.
- 63McNamara LM. Perspective on post-menopausal osteoporosis: establishing an interdisciplinary understanding of the sequence of events from the molecular level to whole bone fractures. J R Soc Interface 2010; 7: 353–72.
- 64Breuil V, Ticchioni M, Testa J, Roux CH, Ferrari P, Breittmayer JP et al. Immune changes in post-menopausal osteoporosis: the Immunos study. Osteoporos Int 2010; 21: 805–14.
- 65Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS ONE 2012; 7: e44552.
- 66DeSelm CJ, Takahata Y, Warren J, Chappel JC, Khan T, Li X et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J Cell Biochem 2012; 113: 2895–902.
- 67Goswami J, Hernandez-Santos N, Zuniga LA, Gaffen SL. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur J Immunol 2009; 39: 2831–9.
- 68Billich A. Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs 2007; 10: 53–9.
- 69Ivanov S, Linden A. Interleukin-17 as a drug target in human disease. Trends Pharmacol Sci 2009; 30: 95–103.
- 70Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006; 12: 382–8.
- 71Laan M, Lotvall J, Chung KF, Linden A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br J Pharmacol 2001; 133: 200–6.
- 72Prause O, Laan M, Lotvall J, Linden A. Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells. Eur J Pharmacol 2003; 462: 193–8.
- 73Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol 1999; 163: 1521–8.
- 74Kageyama Y, Takahashi M, Torikai E, Suzuki M, Ichikawa T, Nagafusa T et al. Treatment with anti-TNF-alpha antibody infliximab reduces serum IL-15 levels in patients with rheumatoid arthritis. Clin Rheumatol 2007; 26: 505–9.
- 75Deselm CJ, Zou W, Teitelbaum SL. Halofuginone prevents estrogen-deficient osteoporosis in mice. J Cell Biochem 2012; 113: 3086–92.
