GENETIC ANALYSIS OF VERTEBRAL STRENGTH

虽然许多环境因素（即，虽然在生长过程中，骨骼的脆弱性（如饮食和运动）会影响骨骼的积累，但对双胞胎的研究已经确定，大约70%的骨矿物质密度的变异是基于遗传的，但在确定与骨骼脆弱性有关的基因之前，还有很多工作要做。 一个有用的策略，揭示复杂的基因相互作用，有助于骨脆性采用近交系小鼠不同的骨矿物质密度和强度。 近交系内的个体是相同的“双胞胎”，它们的环境可以被密切控制。 股骨骨密度显著不同的两种近交系小鼠是C3 H/HeJ或C3 H（高骨密度）和C57 BL/6 J或B6（低骨密度）。 这些近交系之间的计划交配允许遗传等位基因的分离;祖先中对BMD或骨强度重要的等位基因将影响后代中的这些性状。 我们的初步数据表明，B6和C3 H菌株都含有促进高和低椎骨强度的等位基因。 我们的研究结果还表明，股骨中段和椎骨强度是由不同的基因调控的。 因此，我们认为在生长发育过程中，皮质骨和松质骨的微观结构存在着不同的遗传调控。 我们将检验以下假设：1）与股骨的骨矿物质密度相比，椎骨脆性由不同的基因调节，这是一种先前表征的表型; 2）影响椎骨脆性的B6和C3 H等位基因可以在同类小鼠品系中分离出来; 3）B6和C3 H等位基因影响椎骨的皮质和小梁显微结构组织，从而影响椎骨脆性;（4）在快速生长期（2-26周龄），脊椎生物力学特性和显微结构组织的遗传差异在小鼠中变得明显。 我们将使用数量性状基因座（QTL）分析的F2人口从C3 H和B6祖株，以确定基因型（B6和C3 H等位基因）和表型之间的相关性，从腰椎的生物力学测试。 将使用生物力学试验和显微计算机断层扫描（muCT）对来自B6 C3 H-F2群体的同源品系和重组近交品系进行表征，以评价股骨和椎骨微观结构。 最后，将使用muCT和生物力学测试分析不同近交系小鼠在生长和发育过程中对股骨和椎骨微结构的遗传效应。

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.