Estrogen receptor Alpha/Beta antagonism in osteoblasts

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DESCRIPTION (provided by applicant): Estrogen is a key regulator in the growth and maintenance of bone mass in both sexes. Two isoforms of estrogen receptor, ERalpha and ERbeta, mediate the transcriptional effects of estrogen by binding 1 7-beta.estradiol (E2) and subsequently binding to specific elements within the regulatory regions of genes. Although we, and others, have shown that ERalpha and ERbeta are functional in osteoblasts, little data are available concerning the interactions of ERalpha and ERbeta in bone. Recent gene deletion experiments in mice suggest that the ERalpha and ERbeta isoforms may have opposing actions on bone, by analogy with the A and B isoforms of PR, where PR-A is an inhibitor of PR-B. One mechanism to explain the potential antagonistic effects of ERalpha and ERbeta would involve the differential recruitment of steroid receptor coactivators (SRCs), which transmit the transcriptional signal to the basal transcriptional machinery. Therefore, the purpose of this research proposal is to understand the functions of ERalpha/alpha and ERbeta/beta homodimers in human osteoblasts and to understand the effects of the ERalpha/beta heterodimer on gene transcription in human osteoblasts. The project will attempt to address these basic biological questions using three approaches: 1) to understand the effects of ERalpha/beta heterodimers on the transcriptional potential at canonical estrogen response elements (EREs) and at SP1/(ERE1/2) sites in hFOB and MG-63 cell lines; 2) determine the recruitment of steroid receptor coactivators (SRCs) by various ER homo- and heterodimers; and finally 3) determine the in vivo consequences of ERalpha/alpha, ERbeta/beta and ERalpha/beta expression in human OB cells using gene chip technology.