Chronic alcohol abuse results in bone loss and, should a fracture occur, impaired bone healing. Studies in the Turner (sponsor) laboratory suggest that the detrimental effects of alcohol on bone in adult rats are due, in part, to disturbed growth hormone (GH) signaling. In addition to its direct bone anabolic effects, GH mediates the deposition of the important osteoblast growth factor, insulin-like growth factor-l (IGF-I), into bone matrix. The release of IGF-I from the matrix by the action of osteoclasts, in turn, plays a critical role in coupling of bone formation to bone resorption during bone remodeling. In the adult, GH helps maintain bone mass and quality by regulating the balance between bone formation and resorption. GH plays an additional role in the growing skeleton by regulating the net acquisition of bone. Alcohol consumption, especially binge drinking, is very common in adolescents. Although this behavior is generally transient and does not lead to alcoholism, it nevertheless can have undesirable long-term consequences to the skeleton. The long-term goal of the Turner laboratory is to identify pathways mediating skeletal effects of alcohol abuse. The goal of my postdoctoral research is to test the hypothesis that alcohol impairs GH signaling in osteoblasts. This hypothesis will be tested in vitro using human osteoblasts (hFOB cells) and in vivo in male adolescent rats. The specific aims of the proposed research are to: Specific Aim 1: Determine the dose response effects of alcohol on GH-mediated increases in proliferation, differentiation, IGF-I synthesis and nodule formation by hFOB cells. These studies will test the hypothesis that alcohol has a direct inhibitory effect on the bone anabolic response to GH. The results will set the stage for future studies directed toward uncovering the detailed molecular mechanism(s) by which alcohol inhibits GH signaling. Specific Aim 2: Measure the effects of binge drinking on GH-mediated stimulation of osteoblast differentiation and activity in GH-deficient hypophysectomized adolescent rats. These studies will test the hypothesis that adolescent rats are very sensitive to the inhibitory effects of alcohol on bone formation because of their requirement for high levels of GH. Specific Aim 3: Determine the long-duration effects of chronic adolescent binge drinking on peak bone mass, IGF-I levels in bone matrix, bone mechanical properties and turnover. These studies will test the hypothesis that chronic binge drinking reduces the content of IGF-I in bone matrix which, in turn, is associated with impairment of bone remodeling and bone quality even after alcohol is withdrawn. These novel studies will critically evaluate the role of disturbed GH in mediating the detrimental effects of alcohol on bone growth and will critically test a plausible mechanism for alcohol-impaired bone remodeling. [unreadable] [unreadable] [unreadable]