GENETIC DETERMINATION OF SKELETAL FRAGILITY

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DESCRIPTION (Adapted from the Applicant's Abstract): The purpose of this study is to determine the genetic link between skeletal fragility and the structural and compositional properties which contribute to bone fracture. A/J inbred mice exhibit significantly reduced post-yield deformation (a measure of bone brittleness) in whole bone bending tests compared to femurs from C57BL/6J mice. The investigator hypothesizes that the difference in bone fracture properties between A/J and C57BL/6J are due to genetically determined variations in matrix structure and composition. To test this hypothesis, he will first identify the histological and compositional properties that are responsible for the mechanical differences between A/J and C57BL/6J femurs, by experimentally measuring fracture and damage mechanisms, at both the whole bone and the tissue level, and comparing the results with tissue organization and composition parameters. Second, he will conduct a genetic analysis, using recombinant inbred and consomic strains, to determine the number of genes responsible for the differences in fracture behavior and, perhaps, identify candidate genes. Third, he will determine if the matrix alterations responsible for the A/J phenotype are inherited by quantifying the structure and composition of femurs for the recombinant and consomic strains exhibiting the A/J phenotype. Ultimately, the applicant's goal is to make significant contributions to the understanding of skeletal fragility in several ways: (1) identifying alterations in tissue organization which disrupt normal fracture behavior will provide an alternative basis for diagnosis of individuals in the normal population who are at risk of fracture; (2) identifying a genetic link between tissue organization and altered fracture properties provides the basis for future studies which identify how subtle variations in genetic expression are mediated (e.g., physical activity, nutrition, hormonal status, mutations, etc.); and (3) identifying a genetic basis for skeletal fragility may lead to a better understanding of how to customize treatment modalities to accommodate those individuals who are resistant to traditional treatment strategies.