Binge drinking of alcoholic beverages is prevalent among both adolescents and adults, but little is known about the effects that binge drinking with its associated high blood alcohol levels has on skeletal health. Our long-term goal is to characterize the damaging effects of binge alcohol on the adolescent, adult and osteopenic adult skeleton by identifying gene signature patterns that detect binge alcohol-induced bone loss and attenuation of bone damage with therapeutic agents. Our hypotheses are: 1. Binge alcohol exposure causes bone damage that is detectable in its early stages by a unique gene signature profile. 2. Prevention of binge alcohol-induced bone damage with targeted anti-resorptive therapy modulates the expression of a subset of these bone-specific binge alcohol-regulated genes, producing a novel signature profile reflective of the effect of binge alcohol on bone resorption. We base these hypotheses on preliminary data showing: 1) Identification of unique gene expression profiles in bone from adult male rats given alcohol in a binge-like pattern and, 2) Modulation of a subset of alcohol-regulated genes by concurrent anti-resorptive therapy. Based on these observations, our experimental focus is on the identification of gene signatures that detect early binge alcohol-induced bone damage in adolescent, adult and osteopenic adult rats. Gene signatures characteristic of alcohol-induced bone loss and therapeutic intervention will allow early detection of bone damage and provide information allowing identification of novel therapeutics, leading to rational, targeted treatment of bone loss due to alcohol abuse and other causes. ? ? The specific aims of this proposal are to: 1. Identify binge alcohol-induced, bone damage-related gene signatures in adolescent rats. We will identify bone-specific signature patterns that detect the damage caused by binge alcohol to bone (decreased bone density and compressive strength) in male and female adolescent rats. 2. Characterize gene signatures in binge alcohol damaged and therapy-protected adult rat bone. Binge alcohol-related bone-specific signatures may differ with developmental stage, thus we will use adult male and female rats to identify new bone signature patterns related to both binge alcohol-specific bone damage and modulation of signature patterns with anti-resorptive (osteoprotegerin) therapy in adult animals. 3. Compare gene signature profiles of binge alcohol-induced and ovariectomy-induced bone damage. We will identify bone-specific signatures in ovariectomized (OVX) rats with and without binge alcohol treatment, allowing us to define similarities and differences in the molecular pathways leading to pathologic bone loss caused by the distinct, additive bone damaging insults of binge alcohol exposure and estrogen deficiency. ? ? ?
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