Bone undergoes a continuous cycle of remodeling, and recent advances have elucidated many of the molecular mechanisms that regulate this process. A number of pathologic conditions in which the immune system is chronically activated have adverse effects on bone, including rheumatoid arthritis (RA) and periodontal disease. Therefore, in order to develop optimal avenues of intervention and treatment in diseases involving bone loss, it is of great importance to understand immune factors that control bone turnover. A highly complex network of inflammatory cytokines controls bone homeostasis, and strategies aimed at blocking such cytokines have shown clinical success for the treatment of RA. Recently, a new family of bone-acting cytokines was described, the founding member of which is interleukin (IL)-17. Strikingly, both Il-17 and its receptor (IL-17R) are distinct in sequence from other cytokine families (e.g., the TNF or IL-1/Toll-like receptor families). Like TNFalpha and IL-1beta, IL-17 exerts potent effects on bone and is involved in the pathogenesis of RA. In addition, IL-17 triggers the production of other cytokines, chemokines and inflammatory mediators (e.g., IL-6, IL-8, LIX/CSCL5 and PGE2), and also synergizes with various cytokines (e.g., TNFalpha, IL-1beta and IFNgamma). However, despite its central role in inflammation, very little is known about the mechanisms of action and physiological functions of this intriguing cytokine family. Knockout mice provide a powerful genetic tool with which to dissect the roles of individual genes in complex physiological processes. Recently, the IL-17R knockout mice were described. We have obtained these mice and propose to use them to address two important aspects of IL-17R-mediated signaling. First, molecular studies of the IL-17R have been hampered by the fact that it this receptor ubiquitously expressed. Therefore, we will use murine embryonic fibroblast (MEF) lines and primary calvarial osteoblasts derived from these mice to perform structure-function analyses of the IL-17R in order to define contributions of specific receptor subdomains to signal transduction. Second, no studies to date have examined bone turnover in these mice. Accordingly, we will examine the contribution of IL-17R signaling to bone metabolism in vivo using a periodontal model of bone loss. Collectively, these studies will shed light on the function of a novel family of cytokine receptors, as represented by the IL-17R.
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