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

描述(申请人提供)：转化生长因子-β可诱导早期基因-1(TIEG)是最初从人成骨细胞中克隆的Kruppel样转录因子家族的成员，已知在转录调控和转化生长因子-β介导的Smad信号转导中发挥重要作用。在成骨细胞中，雌激素能迅速诱导TIEG，而且这种诱导似乎是通过雌激素受体-β的作用而特异性地实现的。通过对TIEG缺失型小鼠的发育和鉴定，我们发现雌性动物的骨骼比野生型的小鼠要弱得多，体积更小，密度更低。有趣的是，在雄性动物中没有检测到这些差异，这意味着性激素和TIEG表达的丧失在观察到的性别特定的骨表型中起到了作用。基于上述观察，本研究的目的是进一步确定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，并阐明雌激素受体-β特异性诱导TIEG的机制。

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.