While many environmental factors (i.e., diet and exercise) affect bone accumulation during growth, studies in twins have determined that about 70 percent of the variability in bone mineral density is genetically based, yet there is still much work to be done before the genes linked to bone fragility are identified. One useful strategy for uncovering the complex gene interactions contributing to bone fragility employs inbred strains of mice differing in bone mineral density and strength. Individuals within an inbred strain are identical """"""""twins"""""""" and their environments can be closely controlled. Two inbred strains of mice with substantially different femoral bone densities are C3H/HeJ or C3H (high bone density) and C57BL/6J or B6 (low bone density). Planned matings between these inbred strains allow the segregation of genetic alleles; alleles important for BMD or bone strength in the progenitors will affect those traits in the offspring. Our preliminary data demonstrate that both B6 and C3H strains contain alleles that promote both high and low vertebral strength. Our results also suggest that midshaft femoral and vertebral strengths are regulated by different genes. As a result, we propose that there is differential genetic regulation of cortical and trabecular bone microstructures during growth and developement. We will test the following hypotheses: 1) vertebral fragility is regulated by different genes compared to bone mineral density of the femur, a phenotype that was previously characterized; 2) B6 and C3H alleles that affect vertebral fragility can be isolated in congenic strains of mice; 3) B6 and C3H alleles affect both cortical and trabecular microstructural organization of the vertebrae and thus vertebral fragility; 4) the genetic differences in vertebral biomechanical properties and microstructural organization become apparent in mice during the rapid growth phase (2-26 wks of age). We will use quantitative trait loci (QTL) analysis of an F2 population from C3H and B6 progenitor strains to determine correlations between genotype (B6 and C3H alleles) and a phenotype determined from biomechanical testing of the lumbar vertebrae. Congenic strains and recombinant inbred strains from the B6C3H-F2 population will be characterized using biomechanical testing and micro-computed tomography (muCT) to evaluate femoral and vertebral microstructure. Finally, the genetic effects on femoral and vertebral microstructure during growth and development will be analyzed for different inbred strains of mice using muCT and biomechanical testing.
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