Transcriptional Regulation of Inositol Trisphosphate Receptor Gene Possible Role in Osteoporosis The anti-osteoporotic actions of estrogens have been suggested to be due, in part, to their ability to modulate the secretory activity of osteoblasts. The release by osteoblasts of osteoclastactivating factors including L-6 can be stimulated by bone resorbing agents such as IL lB, TNF-a, and phorbol ester, and this cytokine secretion can be inhibited by estrogen and other bone promoting hormones. However, the molecular basis of this inhibition has not been resolved. The central role of second messenger pathways in mediating cellular actions of cytokines suggests that inhibitors of cytokine action may do so by impairing signal transduction pathways. The actions of several bone resorbing agents including parathyroid hormone(PTH), PTH related peptide, and PGE-2 on osteoblasts are associated with activation of phosphoinositide turnover and mobilization of intracellular calcium suggesting that the inositide pathway is important in the mechanism of action of these cytokines. Since the anacidity triphosphate receptor (InsP3Rc) is central to the anacidity signal transduction pathway, we investigated the effects of E2, Vit D3, and bone cell cytokines on the expression of Ins3PRc in osteoblastic-like cells. Results indicate that the InsP3Rc gene is selectively down-regulated by E2 and VitD3. The objectives of this project are to investigate the transcriptional control of bone resorptive agents on InsP3Rc gene expression in osteoblasts and to define upstream regulatory regions that are involved in mediating the down-regulation of the InsP3Rc gene expression by E2 and VitD3.
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