Role of aTGF-beta Regulated Gene in human and mouse osteoblasts and skeleton

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DESCRIPTION (provided by applicant): TGFb, plays a pivotal role in skeletal growth, osteoblast (OB) differentiation, as well as the onset and progression of periodontitis, a main cause for tooth loss in adults. In spite of its role in bone biology and periodontal tissue remodeling, the molecular mechanisms of action of TGFb in bone tissue are not fully understood. During this laboratory's investigations of estrogen (E2) and TGFb actions on OBs, we discovered and characterized the novel TGFb Iducible 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 revealed that TIEG protein activates the TGFb/Smad pathway via transcriptional repression of Smad 7 and activation of Smad 2 and regulates the expression of other important OB marker genes. In order to better understand the function of TIEG in bone, we have generated TIEG-null (TIEG-/-) mice and found that the females, but not males, have smaller and weaker bones, classified as an osteopenic pheontype relative to wild-type littermates. In this past year, we reported that calvarial-derived OBs 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 and could be involved in the gender specific osteopenic phenotype observed 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 OB, and 4) the effects of gonadectomy of male and female TIEG-/- mice on the skeletal phenotype. The completion of these studies should help determine the biological role of TIEG in OB functions as well as skeletal development and maintenance. In addition, these studies should provide new insights into the mechanisms of E2 and TIEG regulation of Runx2 expression and their contribution to bone disease, including periodontitis and osteoporosis.