부산대학교 도서관

Summary: Further studies in this thesis implicate IL-17 signaling in osteoporosis. Although not traditionally thought of as an inflammatory disease, estrogen deficiency osteoporosis is partially mediated by T cells, at least in mice (Weitzmann and Pacifici, 2007). Th17 cells, which secrete IL-17, mediate a number of inflammatory and autoimmune conditions, including arthritis-mediated bone destruction. We find IL-17 critical in the pathogenesis of bone loss due to estrogen deficiency. IL-17 receptor deficient mice are protected from bone loss after ovariectomy, as are mice treated with a neutralizing IL-17 antibody. Mice treated with a small molecule inhibitor of IL-17 production are similarly protected. The effect of IL-17 on osteoclasts is indirect, via osteoblastic upregulation of RANKL. The SEFIR domain of IL-17R is critical for osteoblast-mediated osteoclast formation and RANKL production. The adaptor protein Act1, specifically its SEFIR domain, is required for osteoblast-mediated osteoclast formation in response to IL-17, and Act1-/- mice are also protected from bone loss induced by estrogen deficiency.