It is believed that phytoestrogens have selective estrogen receptor modulatory activity and, hence, the compounds have been classified by some as SERMs. In this highly hypothesis-driven application, the principal investigator postulates that phytoestrogens affect osteoclastogenesis by interacting with estrogen receptors on supporting osteoblasts, thus reducing their expression of osteoclastogenic cytokines, such as CSF-1 (that activates the fms receptor) or RANK-ligand (that activates the NF-kB pathway. He also hypothesizes that phytoestrogens, such as genistein, in addition to their action on the estrogen receptor, also inhibit tyrosine kinase through a non-estrogen receptor mechanism. Thus, in Specific Aim 1, the applicant proposes to assess the effects of phytoestrogens, genistein and daidzein, on (a) osteoblastic production of CSF-1 and RANK-ligand, (b) osteoclastic receptors and downstream signals for CSF-1 and RANK-L, and (c) the processes of osteoclastogenesis and osteoclastic bone resorption.
In Specific Aim 2, the principal investigator intends to study the activity of phytoestrogens on osteoclast development and function when estrogen receptors are either eliminated through antisense approaches, or through the use of a specific antagonist, IC182780. In the same aim, the research team will also compare the binding of the two phytoestrogens, genistein and daidzein, in competition assays for the presence or absence of estrogen receptors.
In Specific Aim 3, the applicant proposes to characterize the non-estrogen receptor -mediated osteoclastic effects of phytoestrogen, specifically on osteoclast acid secretion in intact cells, and in isolated osteoclast membranes. Thus, through a systematic and logically set series of experiments, the principal investigator proposes to clarify a role for phytoestrogens in bone cell regulation.
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