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

aTGF-β调节基因在人和小鼠成骨细胞和骨骼中的作用

• 批准号: 7258157
• 负责人: THOMAS C SPELSBERG
• 金额: $ 35.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258157
• 关键词: Adult; Alkaline Phosphatase; Animals; Architecture; Binding; Biological; Biology; Bone Density; Bone Diseases; Bone Marrow; Bone Mineral Contents; Bone Tissue; Calvaria; Cells; Data; Decompression Sickness; Defect; Estrogen Receptors; Estrogens; Family; Female; Femur; Fracture; Funding; Gender; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; Gonadal Steroid Hormones; Growth; Growth Factor; Hormone replacement therapy; Human; Interferon Gamma Receptor Beta Chain; Investigation; Laboratories; Maintenance; Marrow; Mediating; Messenger RNA; Molecular Mechanisms of Action; Molecular Profiling; Mus; Nuclear; Numbers; Orchiectomy; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Pathway interactions; Periodontitis; Phenotype; Phosphoproteins; Play; Protein Isoforms; Protein Overexpression; Proteins; Rate; Regulation; Regulatory Element; Relative (related person); Reporting; Research Personnel; Role; Signal Transduction; Skeletal Development; Skeletal system; Skeleton; Staging; Standards of Weights and Measures; Stromal Cells; Testing; Tissues; Tooth Loss; Wild Type Mouse; base; bone; cell type; gene repression; insight; male; member; mineralization; mouse model; novel; osteoclastogenesis; programs; restoration; sex; spine bone structure; tibia; transcription factor

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.

描述（由申请人提供）：TGFB在骨骼生长，成骨细胞（OB）分化以及牙周炎的发作和进展中起关键作用，这是成人牙齿脱落的主要原因。尽管它在骨骼生物学和牙周组织重塑中的作用，但尚未完全了解TGFB在骨组织中的作用的分子机制。在该实验室对OBS的雌激素（E2）和TGFB作用的研究中，我们发现并表征了新型的TGFB可识别的早期基因-1（Tieg），是Kruppel转录因子家族的成员（KLF-10）。在OBS中的扎格表达被E2，TGFB和BMP诱导。在过去的资金期间，我们透露，扎格蛋白通过对SMAD 7的转录抑制和SMAD 2的激活来激活TGFB/SMAD途径，并调节其他重要的OB标记基因的表达。为了更好地理解骨头在骨骼中的功能，我们已经产生了束带（拉紧 - / - ）小鼠，发现女性而不是雄性的骨骼较小，骨骼较小，骨骼较小，被归类为相对于野生型窝窝的骨质减少植物。在过去的一年中，我们报告说，钙典写的obs具有显着降低的矿物质和支持破骨细胞生成的能力。这些观察值的进一步表征显示，Runx2，Osterix，碱性磷酸酶和其他重要的OB标记基因的表达水平降低。最近，我们证明了Tieg能够直接调节Runx2的转录，并且该Runx2至少部分原因是绑扎 - / - OB矿化中观察到的缺陷。我们的初步研究表明，E2在雌激素受体（ER）同工型特定方式中诱导绑带的表达。最后，E2还诱导了Runx2在野生型OBS中的表达，但没有诱导绑扎 - / - obs中的表达，这表明绑扎在介导骨中E2作用中的重要作用。基于这些数据，我们的假设是，绑扎的E2调节以及随后的Runx2的绑带调节，至少部分是指观察到的OBS中观察到的缺陷，并且可以参与牵引 - / - 小鼠中观察到的性别特异性骨质减少表型。为了检验这一假设，我们计划确定：1）Runx2表达在绑扎中观察到的缺陷中具有的liTG调节作用在绑扎 - / - obs中观察到的缺陷，2）E2调节扎格表达对绑带的贡献 - / - ob表型 - / - OB表型，3）绑扎在OB中的E2 E2 tie and the ob和4）tieg的作用在OB中的E2 runx2 runx and the ob/4）效果 - 4）骨骼表型。这些研究的完成应有助于确定扎格在OB功能以及骨骼发育和维持中的生物学作用。此外，这些研究应提供有关E2和Runx2表达调节机制的新见解及其对骨骼疾病的贡献，包括牙周炎和骨质疏松症。