REGULATION OF BONE BALANCE BY ESTROGEN AND ANTIESTROGENS

描述：(改编自《调查者摘要》)雌激素 对维持成人骨骼的正常骨骼平衡是必不可少的。 缺乏这种荷尔蒙会导致骨转换率增加， 骨吸收增加。由此产生的骨量减少是一个重要的 绝经后骨折风险增加的影响因素 女人。ES替代疗法降低中国人骨质疏松的风险 绝经后妇女通过重新建立正常的骨转换，但 治疗的潜在健康益处必须与 增加威胁生命的副作用的风险，包括乳房和 子宫癌。一种令人兴奋的新方法来减少不受欢迎的一面 激素替代疗法的作用是替代组织特异性 天然ES的部分ES激动剂。抗雌激素药他莫昔芬()是 主要是ES激动剂的ES类似物的示例 骨骼和肝脏在相同的处理条件下 子宫和乳房上的敌手。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 其重要临床表现、雌激素的作用机制 骨的周转情况尚不清楚。 拟议研究的一个目标是表征ES和 部分ES激动剂对去卵巢大鼠骨细胞动力学的影响 大鼠模型，以揭示其介导的细胞机制。 卵巢切除后的骨质丢失。申请者将依靠 动态骨组织形态计量学的应用--~3H-胸腺嘧啶核苷 无线电自显影术.稳态信息电平的Northern分析 骨蛋白，放射性标记化合物的摄取和保留(~3H- Pro/14C-Pro)转化为骨基质，以及血清和尿液标志物 骨骼新陈代谢。这项拟议研究的第二个目标是测试 ES通过诱导ES受体作用于骨靶细胞的假说 (Er)介导级联。根据这一模式，ES规定了 相对较少的关键基因的表达 表达(或压抑)最终影响的数字要大得多 他们建议测试ES作用的级联模型 成年大鼠骨骼组织内质网数量调节的研究 以及确定推测的早期表达的顺序变化 调控基因(核原癌基因)、中间基因(如生长 因素)和晚期基因(例如，骨基质蛋白)。又一次考验 级联假设将通过比较以下因素的影响来实现 混合ES激动剂/拮抗剂对骨骼早、中、晚期基因的影响 肝脏和子宫。预计不同组织之间的差异 在对部分ES激动剂的反应中， 激素诱导的级联反应的模式。这些研究将依赖于 Northern分析和定量PCR。据预计， 这些研究结果将进一步阐明ES的作用机制。 论骨的周转与有效新品的合理设计 激素替代疗法治疗骨质疏松症的方法。

DESCRIPTION: (Adapted From Investigator's Abstract) Estrogen (Es) is essential to maintain normal bone balance in the adult skeleton.A deficiency of this hormone results in increased bone turnover and a net increase in bone resorption. The resulting osteopenia is an important contributing factor to the increased fracture risk in postmenopausal women. Es replacement therapy reduces the risk of osteoporosis in postmenopausal women by re-establishing normal bone turnover, but the potential health benefits of treatment must be weighted against an increased risk of life threatening side effects, including breast and uterine cancer. An exciting new approach to reduce the undesirable side effects of hormone replacement therapy is to substitute tissue-specific partial Es agonists for natural Es.The "antiestrogen" tamoxifen (TAM) is an example of an Es analog that is primarily an Es agonist on the skeleton and liver under the same treatment conditions for which it is an antagonist on the uterus and breast. The mechanism for the mixed Es agonist/antagonist effects of TAM is unknown. Furthermore in spite of its important clinical manifestations, estrogen's mechanism of action on bone turnover is unclear. A goal of the proposed research is to characterize the effects of Es and selected partial Es agonists on bone cell dynamics in the ovariectomized rat model in order to reveal the cellular mechanism which mediates the bone loss following ovariectomy. The applicants will rely upon the application of dynamic bone histomorphometry, 3H-thymidine radioautography, Northern analysis of steady-state message levels for bone proteins, uptake and retention of radiolabeled compounds (3H- proline/14C-proline) into bone matrix, and serum and urine markers for bone metabolism. A second goal of the proposed research is to test the hypothesis that Es acts on bone target cells by inducing an Es receptor (ER)-mediated cascade. According to this model; Es regulates the expression of a relatively small number of critical genes whose expression (or repression) ultimately influences a much larger number of genes.They propose to test this cascade model for Es action in skeletal tissues of adult rats by investigating regulation of ER number and determining sequential changes in expression of putative early regulated genes (nuclear proto-oncogenes), middle genes (e.g. growth factors) and late genes (e.g., bone matrix protein). A further test of the cascade hypothesis will be performed by comparing the effects of mixed Es agonists/antagonists on early, middle and late genes in bone, liver and uterus. It is anticipated that the tissue-specific differences in the response to partial Es agonists result from chantes in the pattern of the hormone-induced cascade. These studies will rely upon Northern analysis and quantitative PCR. It is anticipated that the results of these studies will further clarify the mechanism of Es action on bone turnover and aid in the rational design of effective new approaches to hormone replacement therapy for osteoporosis.