DOSE RESPONSE EFFECTS OF ALCOHOL ON BONE METABOLISM

申请人摘要：拟议中的大鼠研究的目标是 检查负责调解的细胞和分子机制 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、骨量减少和骨折增加有关 风险。适度饮酒者的健康风险还不太确定，但 已经描述了有益的和有害的影响。更好的 了解风险和收益很重要，因为大多数 我们的成年人是偶尔到适度饮酒的人。假设 在这些研究中得到验证的是酒精能抑制骨骼的形成 重塑，从而降低整体骨骼的周转率。此操作 可使骨骼周转率高的个人受益(例如，患有 绝经后骨质流失)。此外，我们假设酒精会抑制 骨改建中骨形成阶段的成骨细胞活性 周期(这一行动可能会增加骨质疏松症的风险 与慢性酒精滥用所观察到的骨量减少一致)。在 在分子水平上，骨重建的变化被认为是导致 因为酒精干扰了成骨细胞衍生的信号肽的表达 (骨骼生长因子和细胞因子)，它们结合了部位和数量 骨形成与骨吸收的位置和程度有关。这些 假说将通过在大鼠身上建立：1)剂量反应 酒精对骨量、骨细胞数和骨密度的长期影响 活动、建筑、骨诱导活动和机械 特性；2)酒精对骨重建的短期影响；3)影响 酒精对成骨细胞和破骨细胞在骨组织中募集的影响 重塑；4)酒精对相关基因表达的影响。 成骨细胞衍生的细胞信号肽。

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.