ESTROGEN METABOLITES EFFECTS ON BONE

合理设计预防和/或治疗骨质疏松症的创新方法的一个严重障碍是绝经后骨丢失的特发性。绝经是骨质疏松症最重要的危险因素。然而，并不是所有绝经后妇女都发生骨质疏松性骨折，这表明月经周期的停止不足以完全解释这种疾病。我们的工作假设是雌激素的从头产生和代谢是影响绝经后骨质流失率的最重要因素之一。雌酮（E1）及其代谢产物16 α-羟基雌酮（16 α-OHE 1）和2-羟基雌酮（2-OHE 1）是绝经后妇女体内含量最丰富的雌激素。16 α-OHE 1最近被证明是绝经后骨质流失的负风险因素（降低风险），而2-OHE 1是正风险因素（增加风险）。2-OHE 1在卵巢切除（OVX'd）大鼠中不具有雌激素活性。相比之下，16 α-OHE 1似乎是一种组织选择性雌激素激动剂，其活性特征与抗乳腺药物他莫昔芬相似; 16 α-OHE 1是一种对骨骼和肝脏比对生殖组织更有效的雌激素激动剂。这些观察结果表明，2-OHE 1和16-α-OHE 1的骨骼活性差异是绝经后女性骨量与这些代谢物循环水平之间观察到的相关性的原因。我们建议在卵巢完整和OVX'd大鼠中检验这一假设。具体目的是确定2-OHE 1和16 α-OHE 1对骨和其他雌激素靶组织中即刻反应基因表达的剂量反应效应;并确定雌酮代谢产物对骨结构、转换和强度的长期影响。拟议的研究将描述可能的细胞作用机制。这些研究的结果很可能与妇女有关，因为绝经后骨质流失和OVX诱导的大鼠骨质流失之间的相似性，以及先前大鼠模型在预测人类骨骼对雌激素激动剂和标记物的反应以预测绝经后骨质流失率方面所取得的成功; 2）通过改变饮食或通过药物干预来操纵雌酮代谢可能是减少骨丢失的有价值的工具;和3）16 α-OHE 1的类似物可用于预防和治疗绝经后骨质疏松症。

A serious obstacle to the rational design of innovative approaches for preventing and/or treating osteoporosis is the idiopathic nature of postmenopausal bone loss. Menopause is the most important risk factor for osteoporosis. However, not all postmenopausal women develop osteoporotic fractures indicating that cessation of the menstrual cycle is insufficient to fully account for the disorder. Our working hypothesis is that the denovo production and metabolism of estrogens are among the most important factors influencing the rate of postmenopausal bone loss. Estrone (E1) and its metabolites, 16alpha-Hydroxyl estrone ( (16alpha-OHE1) and 2-hydroxyesterone (2-OHE1), are the most abundant estrogens in postmenopausal women. 16alpha-OHE1 has been recently shown to be a negative risk factor (reduced risk) for postmenopausal bone loss, whereas 2-OHE1 has been positive risk factor (increased risk). 2-OHE1 does not have estrogenic activity in ovariectomized (OVX'd) rats. In contrast, 16alpha-OHE1 appears to be a tissue selective estrogen agonist with a profile of activity similar to the anti-breast drug tamoxifen; 16alpha-OHE1 is a much more effective estrogen agonist on bone and liver than on reproductive tissues. These observations suggest that differences in the skeletal activities on 2-OHE1 and 16-alpha-OHE1 are responsible for the observed association between bone mass and circulating levels of these metabolites in postmenopausal women. We propose to test this hypothesis in ovary intact and OVX'd rats. The specific aims are to determine the dose response effects of 2-OHE1 and 16alpha-OHE1 on the expression of immediate response genes in bone and other estrogen target tissues; and establish the long-term effects of the estrone metabolites on bone architecture, turnover and strength. The proposed research will characterize the probably cellular mechanisms of action. The results of these studies are likely to be relevant to women because of the similarity between postmenopausal bone loss and OVX-induced bone loss in rats, as well as the previous success the rat model has enjoyed for predicting the response of the human skeleton to estrogen agonists and markers to predict the rate of postmenopausal bone loss; 2) manipulation of estrone metabolism by changes in diet or by pharmacological intervention may be a valuable tool for reducing bone loss; and 3) analogs of 16alpha-OHE1 may be useful for prevention and treatment of postmenopausal osteoporosis.