Cellular and Molecular Mechanisms of Inhibin Action on the Skeleton

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DESCRIPTION (provided by applicant): The purpose of this proposal is to identify the cellular and mechanistic actions of Inhibin as it involves bone formation. The focus of this proposal is to determine the molecular mechanisms by which Inhibins exert a bimodal regulation on the skeleton such that short-term exposure represses osteoblastogenesis and long-term continuous exposure stimulates bone formation. The approach will be to determine the cellular basis of the bimodal regulation of Inhibin A on bone turnover in vivo, and then to validate the involvement of three specific genes identified in expression profiling, IGF-1, VEGFA and BMP5 with IGF-1 the priority, to determine their involvement in Inhibin A-regulated bone metabolism. This will be specifically performed by, AIM1: Determining the effects of Inhibin A on the cellular composition of bone and bone turnover across a time course of continuous Inhibin A exposure. AIM 2: Determining the extent to which Inhibin A regulates IGF-1 in vitro and in vivo to alter osteoblastogenesis and bone formation. AIM 3: Determining if the effects of Inhibin A on bone metabolism are mediated by changes in IGF-1, and whether IGF-1 mediates Inhibin A action on the skeleton. The methods involved will include RT and real time PCR, immunoneutralization experiments, static and dynamic histomorphometry, immunohistochemistry and cell cultures. This proposal is a novel and beneficial idea to the bone field. Osteoporosis is a disease that has become a prevalent problem in both men and women. A primary cause of bone loss is loss of gonadal function associated with aging. Recent identification of the anabolic action of Inhibins on bone brings the field one step closer to finding another possible treatment. However, the action is not known. This proposal seeks to identify those mechanisms of action.