Role of sex steroids in female TIEG-null mouse bone loss

性类固醇在雌性 TIEG 缺失小鼠骨质流失中的作用

• 批准号: 7109536
• 负责人: John R. Hawse
• 金额: $ 4.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7109536
• 关键词: biological signal transduction; bone density; chromatin immunoprecipitation; computed axial tomography; estrogen receptors; estrogens; gel mobility shift assay; gender difference; gene induction /repression; genetically modified animals; hormone therapy; laboratory mouse; male castration; neoplastic cell; nonhuman therapy evaluation; osteogenesis; ovariectomy; phenotype; photon absorptiometry; physiologic bone resorption; postdoctoral investigator; protein isoforms; receptor binding; reporter genes; transcription factor; transforming growth factors

DESCRIPTION (provided by applicant): TGF-beta inducible early gene-1 (TIEG) is a member of the Kruppel-like transcription factor family originally cloned from human osteoblasts that is known to play an important role in transcriptional regulation and in TGF-beta mediated Smad signaling. TIEG is rapidly induced by estrogen in osteoblast cells and this induction seems to be specifically through the action of estrogen receptor-beta. Through the development and characterization of TIEG-null mice, we have shown that female animals display significantly weaker, smaller and less dense bones relative to wild-type litter mates. Intriguingly, these differences are not detectable in male animals implying a role for the sex steroids, in combination with the loss of TIEG expression, in the observed gender specific bone phenotype. Based on the above observations, it is the goal of this proposal to further characterize the molecular basis behind the gender specific bone phenotype, to identify the role of estrogen and/or testosterone in this gender specificity and to elucidate the mechanisms by which TIEG is specifically induced by estrogen receptor-beta.

描述（由申请人提供）：TGF-β诱导性早期基因-1（TIEG）是Kruppel样转录因子家族的成员，最初从人成骨细胞中克隆，已知在转录调节和TGF-β中发挥重要作用介导的 Smad 信号传导。 TIEG 被成骨细胞中的雌激素快速诱导，并且这种诱导似乎是通过雌激素受体-β 的作用特异性进行的。通过对 TIEG 缺失小鼠的发育和表征，我们发现雌性动物的骨骼相对于野生型同窝小鼠明显更弱、更小且密度更低。有趣的是，这些差异在雄性动物中无法检测到，这意味着性类固醇与 TIEG 表达缺失相结合，在观察到的性别特异性骨表型中发挥了作用。基于上述观察，本提案的目标是进一步表征性别特异性骨表型背后的分子基础，确定雌激素和/或睾酮在这种性别特异性中的作用，并阐明 TIEG 特异性发挥作用的机制。由雌激素受体-β 诱导。