Regulation of osteoblast function by endothelin-1

描述(由申请人提供)：肿瘤产生内皮素-1(ET-1)通过内皮素A受体(ETA)介导与成骨细胞转移相关的新骨形成。然而，这种情况发生的机制以及ET-1在正常骨重建中的作用尚不清楚，这将是本研究的主题。目的1：ET-1促进新骨生长，但这是通过促进骨祖细胞的增殖、促进向成熟成骨细胞的分化还是通过抑制成骨细胞的凋亡来实现的。目的：研究ET-1对表皮生长因子受体的反式激活作用，以确定1)这是否是刺激成骨细胞活性的重要信号通路；2)雌激素是否调节这一作用。目的：研究Wnt5a和Dickkopf同系物1自分泌信号、β-连环蛋白和钙敏感信号通路在ET-1刺激成骨细胞活性中的作用。目的：利用Cre-loxP系统构建靶向缺失ETA的成骨细胞特异性基因敲除小鼠。由于性类固醇调节ETA阻滞剂的作用，优降糖和去势小鼠将被分析大体解剖和组织学骨骼发育异常。

DESCRIPTION (provided by applicant): Tumor production of endothelin-1 (ET-1) mediates new bone formation associated with osteoblastic metastases through the endothelin A receptor (ETA). However, the mechanisms by which this occurs and the role of ET-1 in normal bone remodeling is unknown, and will be the topic of this investigation. Aim 1: ET-1 stimulates new bone growth but whether this occurs by increased proliferation of osteoprogenitor cells, enhanced differentiation to mature osteoblasts or by inhibition of osteoblast apoptosis will be determined. Aim 2: The transactivation of the epidermal growth factor receptor by ET-1 will be tested to establish 1) if this is an important signaling pathway responsible for stimulating osteoblast activity and 2) whether estradiol modulates this effect. Aim 3: The roles of Wnt5a and Dickkopf homolog 1 autocrine signaling, Beta-catenin and the calcium-sensitive signaling pathways in ET-1 stimulation of osteoblast activity will be tested. Aim 4: The Cre-loxP system was utilized to make an osteoblast-specific knockout mouse with a targeted deletion of ETA. Since sex steroids modulate the effects of ETA blockade, eugonadal and castrated mice will be analyzed for gross anatomic and histologic bone developmental abnormalities.