GENETICS OF GLUCOCORTICOID INDUCED OSTEOPOROSIS IN MICE

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Osteoporosis is a leading cause of morbidity and mortality of older individuals, but susceptibility to osteoporosis varies widely. Several lines of evidence suggest that genetic predisposition contributes about half of this variation. Although chronic glucocorticoid use can lead to a broad range of adverse effects including osteoporosis, these drugs are widely used for many medical conditions including the arthritides. As is the case with involutional osteoporosis, individuals vary widely in their susceptibility to glucocorticoid induced osteoporosis. This project tests the hypothesis that genetic predisposition contributes to glucocorticoid induced osteoporosis in mice. Its goal is to identify, map and ultimately clone genes mediating susceptibility to glucocorticoid induced osteoporosis in mice through the analysis of existing recombinant congenic strain sets. In the first stage of the work, the susceptibilities of the progenitors of the recombinant congenics to glucocorticoid induced osteoporosis, and secondarily other glucocorticoid toxicities, will be determined. In the second stage of the work, the recombinant congenic strain set whose progenitors are most divergent will be analyzed to identify chromosomal regions that harbor genes affecting glucocorticoid induced osteoporosis. In the third stage of the work further breeding will be performed to refine the mapping of the candidate genes and provide the necessary information for their positional cloning. Identifying mouse chromosome regions that contribute to osteoporosis will allow prediction of the corresponding human regions by synteny arguments and facilitate the design of human genetic studies of this problem.