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质流失的特发性。更年期是骨质疏松症最重要的危险因素。然而，并非所有绝经后妇女都会发生骨质疏松性骨折，这表明停止月经周期不足以完全解释这种疾病。我们的工作假设是雌激素的分泌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 -羟雌酮（16 α - ohe1）和2-羟甾酮（2-OHE1）是绝经后妇女中含量最多的雌激素。α - ohe1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-OHE1是正风险因素（增加风险）。2-OHE1在去卵巢大鼠（OVX'd）中没有雌激素活性。相反，16 α - ohe1似乎是一种组织选择性雌激素激动剂，其活性与抗乳腺药物他莫昔芬相似；α - ohe1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，骨骼中2-OHE1和16- α - ohe1活性的差异是绝经后妇女骨量与这些代谢物循环水平之间存在关联的原因。我们拟在卵巢完整大鼠和OVX大鼠身上验证这一假设。具体目的是确定2-OHE1和16 α - ohe1对骨及其他雌激素靶组织中即刻反应基因表达的剂量效应；并确定雌酮代谢物对骨结构、周转率和强度的长期影响。拟议的研究将描述可能的细胞作用机制。这些研究的结果可能与女性相关，因为大鼠绝经后骨质流失与ovx诱导的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志物的反应方面取得的成功，以预测绝经后骨质流失的速度；2)通过改变饮食或药物干预来控制雌酮代谢可能是减少骨质流失的一种有价值的工具；3) 16 α - ohe1类似物可能有助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.