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.