Estrogen (E2) and TGFb play pivotal roles in skeletal growth, osteoblast (OB) differentiation, and bone diseases such as osteoporosis. In spite of their role in OB differentiation and bone remodeling, the molecular mechanisms of E2 and TGFb action in bone tissue are not fully understood. During this laboratory's investigations of E2 and TGFb actions in OBs, we discovered and characterized the novel TGFb Inducible Early Gene-1 (TIEG) as a member of the Kruppel family of transcription factors (KLF-10). TIEG expression in OBs was shown to be induced by E2, TGFb, and BMPs. During the past funding period, we identified an important role for TIEG in mediating TGFb siganling as it represses Smad 7 expression and induces the expression of Smad 2. In order to better understand the function of TIEG in bone, we have generated TIEG-null (TIEG-/-) mice and have found that females, but not males, have smaller and weaker bones, characterized as osteopenic, relative to wild-type littermates. We have reported that calvarial OBs isolated from TIEG-/- mice have a markedly reduced capacity to mineralize bone and to support osteoclastogenesis. Further characterization of these OBs revealed decreased expression levels of Runx2, osterix, alkaline phosphatase, and other important OB marker genes. Recently, we have demonstrated that TIEG is capable of directly regulating the transcription of Runx2 and that Runx2 appears to be, at least in part, responsible for the observed defects in TIEG-/- OB mineralization. Our preliminary studies have shown that E2 induces the expression of TIEG in an estrogen receptor (ER) isoform specific manner. Finally, E2 also induces the expression of Runx2 in wild-type OBs, but not in TIEG-/- OBs, suggesting an important role for TIEG in mediating E2 action in bone. Based on these data, it is our hypothesis that the E2 regulation of TIEG, and the subsequent TIEG regulation of Runx2, is at least in part responsible for the observed defects in OBs which, in turn, leads to a gender-specific osteopenic phenotype in TIEG-/- mice. In order to test this hypothesis, we plan to determine: 1) the role that TIEG regulation of Runx2 expression has on the observed defects in TIEG-/- OBs, 2) the contribution of E2 regulation of TIEG expression to the TIEG-/- OB phenotype, 3) the role of TIEG in mediating E2 activation of Runx2 expression in OBs, and 4) the effects of gonadectomy of male and female TIEG-/- mice on the skeletal phenotype. The completion of these studies will help determine the biological role of TIEG in OB functions as well as skeletal development and maintenance. In addition, these studies will provide new insights into the mechanisms of E2 and TIEG regulation of Runx2 expression and their contribution to bone disease, including osteoporosis.
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