GENETIC ANALYSIS OF VERTEBRAL STRENGTH

虽然许多环境因素(即饮食和锻炼)会影响生长过程中的骨积累，但对双胞胎的研究已经确定，大约70%的骨密度变异是基于遗传的，但在确定与骨骼脆性有关的基因之前，仍有许多工作要做。揭示导致骨脆性的复杂基因相互作用的一个有用的策略是使用骨密度和强度不同的近交系小鼠。近亲繁殖品系中的个体是相同的“双胞胎”，他们的环境可以受到严密的控制。两个近交系小鼠的股骨骨密度有很大的不同，分别是C3H/HeJ或C3H(高骨密度)和C57BL/6J或B6(低骨密度)。这些近交系之间的有计划的配对允许分离遗传等位基因；对后代的骨密度或骨骼强度重要的等位基因将影响后代的这些特征。我们的初步数据表明，B6和C3H菌株都含有促进高强度和低强度脊椎力量的等位基因。我们的结果还表明，股骨干中段和脊椎的强度受不同基因的调节。因此，我们认为在生长发育过程中，皮质骨和松质骨的微结构存在不同的遗传调控。我们将检验下列假设：1)与股骨的骨密度相比，椎体的脆性受到不同基因的调节，这是一种先前已被表征的表型；2)可以在同源品系的小鼠中分离出影响椎骨脆性的B6和C3H等位基因；3)B6和C3H等位基因同时影响椎骨的皮质和松质微结构组织，从而影响椎骨的脆性；4)在小鼠的快速生长期(2-26周龄)，脊椎生物力学特性和微结构组织的遗传差异变得明显。我们将使用数量性状基因座(QTL)分析来自C3H和B6祖系的F2群体，以确定基因型(B6和C3H等位基因)与腰椎生物力学测试确定的表型之间的相关性。来自B6C3H-F2群体的同源菌株和重组近交系菌株将使用生物力学测试和微型计算机断层扫描(MUCT)来鉴定股骨和脊椎的微结构。最后，将利用MUCT和生物力学测试来分析不同近交系小鼠在生长发育过程中对股骨和脊椎微结构的遗传效应。

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.