REGULATION OF BONE BALANCE BY ESTROGEN AND TAMOXIFEN

雌激素在调节卵巢的生长和发育中起着基础性的作用。 骨架的维护。ES缺乏导致骨量减少和IS 老龄化导致骨折风险增加的重要因素 女人。ES替代治疗可降低老年人骨折风险 绝经后妇女保持骨量但潜在的健康 治疗的风险包括增加乳房和子宫的发病率 癌症。将ES的并发症降至最低是可能的。 用组织特异性部分ES激动剂替代。这个 抗雌激素药他莫昔芬()是ES类似物的一个例子，它是一种 在治疗条件下子宫上的ES拮抗剂 骨骼上的激动剂。混合ES的形成机制 的激动剂/拮抗剂作用尚不清楚。此外，尽管 其重要的临床表现、发病机制甚至精确 ES对骨细胞的作用尚不清楚。我们打算测试一下 ES抑制骨转换作用的假说是中介的 通过成骨细胞衍生的生长因子。尽管ES可能会影响 多个生长因子，我们将集中力量研究胰岛素样 生长因子-I(IGF-I)。IGF-I是由骨骼产生的，对骨骼有影响 细胞，并已被证明介导了ES对正常人的许多影响 对子宫和肝脏细胞以及乳腺癌细胞也是如此。这个 骨骼和子宫对反应的差异可能是由于 胰岛素样生长因子-I在不同组织中表达的差异调节 纸巾。此外，ES和生长激素的明显相反作用 (GH)对骨生长的影响可能是由于反对IGF-I的调节 通过各自的荷尔蒙表达。我们将测试这些可能性 1)观察ES和对大鼠胰岛素样生长因子-I表达的影响 在骨和子宫中，2)定位骨中表达IGF-I的细胞， 3)确定ES和的显著抑制作用 对骨基质合成的影响被IGF-I中和；4)测定 ES和是否与GH相互作用调节IGF-I的表达。这个 建议的研究结果可望增加我们的 了解ES调节数字和数字的机制 骨骼细胞的活动，可以促进理性的信息 设计创新的方法来预防和/或治疗 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.