title: Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis.
abstract: Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research, Chattar Manzil, Lucknow, India.
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Tyagi
authors.forename: Kamini
authors.initials: K
authors.lastname: Srivastava
authors.forename: Mohd Nizam
authors.initials: MN
authors.lastname: Mansoori
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004958:Estradiol / Q000172:deficiency*; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010024:Osteoporosis / Q000209:etiology*; D053244:Osteoprotegerin / Q000235:genetics; D010052:Ovariectomy; D053245:RANK Ligand / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C505689:Tnfsf11 protein, mouse; D004958:Estradiol