REGULATION OF BONE BALANCE BY ESTROGEN AND TAMOXIFEN

雌激素（Estrogen，Es）在调节生长和发育中起着重要作用， 保持骨骼。 Es缺乏导致骨质减少， 一个重要的促成因素，增加骨折的风险，在老化 妇女 ES替代治疗可降低骨折风险， 绝经后妇女通过保留骨量，但潜在的健康 治疗的风险包括乳腺癌和子宫癌的发生率增加， 癌 这可能会减少并发症的Es 用组织特异性部分Es激动剂替代。 的 “抗雌激素”他莫昔芬（TAM）是作为雌激素受体的Es类似物的实例。 ES拮抗剂在治疗条件下对子宫的作用 骨骼上的激动剂 混合Es的机制 TAM的激动剂/拮抗剂作用是未知的。 此外，尽管 其重要的临床表现，机制，甚至精确 Es对骨细胞的作用尚不清楚。 我们打算测试 假设Es抑制骨转换的作用是介导的， 成骨细胞衍生的生长因子。 尽管Es可能会影响 多种生长因子，我们将集中精力在胰岛素样 生长因子-I（IGF-I）。 IGF-I由骨产生并对骨有影响 细胞，并已被证明介导许多影响的Es对正常 子宫和肝细胞以及乳腺癌细胞。 的 骨和子宫对TAM反应的差异可能是由于 IGF-I表达的差异调节，在各自的 组织中 此外，Es和生长激素的明显相反作用 (GH)可能是由于IGF-I的相反调节 由各自的荷尔蒙表达。 我们将测试这些可能性 在大鼠中通过：1）确定Es和TAM对IGF-I表达的影响 在骨和子宫中，2）在骨中定位表达IGF-I的细胞， 3)确定Es和TAM的显著抑制作用是否 对骨基质合成的影响被IGF-I抵消，以及4）确定 Es和TAM是否与GH相互作用调节IGF-I的表达。 的 预计拟议研究的结果将增加我们的 理解Es调节数字的机制， 骨细胞的活动，信息，可以加速合理的 制定预防和/或治疗艾滋病毒/艾滋病 绝经后骨质流失

Estrogen (Es) plays a fundamental role in regulating the growth and maintenance of the skeleton. Es deficiency results in osteopenia and is an important contributing factor to the increased fracture risk in aging women. Es replacement therapy can reduce the fracture risk in postmenopausal women by preserving bone mass but the potential health risks of treatment include increased incidence of breast and uterine cancer. It may be possible to minimize the complications of Es replacement with tissue-specific partial Es agonists. The "antiestrogen" tamoxifen (TAM) is an example of an Es analog that is an Es antagonist on the uterus under treatment conditions for which it is an agonist on the skeleton. The mechanism for the mixed Es agonist/antagonist effects of TAM are unknown. Furthermore, in spite of its important clinical manifestations, the mechanisms and even precise actions of Es on bone cells are unknown. We intend to test the hypothesis that the effects of Es to inhibit bone turnover are mediated by osteoblast-derived growth factors. Although Es may influence multiple growth factors, we will concentrate our efforts on insulin-like growth factor-I (IGF-I). IGF-I is produced by and has effects on bone cells and has been shown to mediate many of the effects of Es on normal uterine and liver cells as well as on breast cancer cells. The differences in the response of bone and uterus to TAM may result from the differential regulation of IGF-I expression in the respective tissues. Also, the pronounced opposing actions of Es and growth hormone (GH) on bone growth may be due to opposing regulation of IGF-I expression by the respective hormones. We will test these possibilities in rats by: 1) determining the effects of Es and TAM on IGF-I expression in bone and uterus, 2) localizing the cells that express IGF-I in bone, 3) establishing whether the pronounced inhibitory effects of Es and TAM on bone matrix synthesis are counteracted with IGF-I, and 4) determining whether Es and TAM interact with GH to regulate IGF-I expression. The results of the proposed studies are expected to increase our understanding of the mechanisms by which Es modulates numbers and activities of bone cells, information that could accelerate the rational design of innovative approaches for the prevention and/or treatment of postmenopausal bone loss.