DOSE RESPONSE EFFECTS OF ALCOHOL ON BONE METABOLISM

申请人摘要：在大鼠中进行拟议研究的目的是 检查负责介导的细胞和分子机制， 酒精对骨骼和矿物质代谢的作用。 长期酗酒是 与骨形成抑制、骨质减少和骨折增加相关 风险 适度饮酒者的健康风险还不太确定， 已经描述了有益的和有害的效果。 更好的 了解风险和收益很重要，因为大多数 我们的成年人偶尔也会适度饮酒。 假设， 在这些研究中测试的是，酒精抑制骨的启动 重塑，从而降低骨转换的总体速率。 此操作 可以使具有高骨转换的个体受益（例如，妇女 绝经后骨质流失）。 此外，我们假设酒精抑制 成骨细胞活性在骨重建的骨形成阶段 周期（这种行为可能会增加骨质疏松症的风险， 与慢性酒精滥用时观察到的骨质减少一致）。 在 在分子水平上，骨重建的变化被假定为导致 因为酒精破坏了成骨细胞来源的信号肽的表达 （骨骼生长因子和细胞因子），其将骨形成的部位和数量结合在一起。 骨形成与骨吸收的位置和程度有关。 这些 将在大鼠中通过建立以下模型来检验假设：1） 酒精对骨量、骨细胞数量和 活性、结构、骨诱导活性和机械 性质; 2）酒精对骨重建的短期影响; 3）影响 酒精对骨过程中成骨细胞和破骨细胞的募集的影响 重塑;和4）酒精对与以下相关的基因表达的影响： 成骨细胞来源的细胞信号肽。

APPLICANT'S ABSTRACT: The goal of the proposed research in rats is to examine the cellular and molecular mechanisms responsible for mediating alcohol's actions on bone and mineral metabolism. Chronic alcohol abuse is associated with depressed bone formation, osteopenia and increased fracture risk. The health risks for moderate drinkers are much less certain, but beneficial as well as detrimental effects have been described. A better understanding of the risks and benefits is important because the majority of our adult population are occasional to moderate drinkers. The hypotheses to be tested in these studies are that alcohol inhibits initiation of bone remodeling thereby reducing the overall rate of bone turnover. This action could benefit individuals with high bone turnover (e.g., women with postmenopausal bone loss). Additionally, we postulate that alcohol inhibits osteoblast activity during the bone formation phase of the bone remodeling cycle (this action could increase the risk for osteoporosis and is consistent with osteopenia observed with chronic alcohol abuse). At the molecular level, the changes in bone remodeling are postulated to result because alcohol disrupts expression of osteoblast-derived signaling peptides (skeletal growth factors and cytokines) which couple the site and amount of bone formation to the location and extent of bone resorption. These hypotheses will be tested in rats by establishing: 1) a dose response for the long-term effects of alcohol on bone mass, bone cell numbers and activities, architecture, osteoinductive activity, and mechanical properties; 2) short-term effects of alcohol on bone remodeling; 3) effects of alcohol on recruitment of osteoblasts and osteoclasts during bone remodeling; and 4) effects of alcohol on expression of genes related to osteoblast derived cell signaling peptides.