GENETIC ANALYSIS OF BONE FRAGILITY IN RATS

目前对骨质疏松症的遗传学有相当大的兴趣。遗传学研究中的一个工具是近亲交配的大鼠模型。我们已经发现了一种近交系大鼠(Fischer 344)，与其他几个品系的大鼠相比，它的骨矿密度(BMD)更低，骨骼更脆弱。与Lewis大鼠相比，成年雌性Fischer大鼠的骨密度降低12-14%，股骨中段脆性增加30%，股骨和腰椎骨折做功减少40%。Fischer大鼠在股骨和脊椎的几何形状上也与Lewis大鼠不同。费舍尔和刘易斯品系是筛选微卫星标记的大鼠品系之一，这使得使用数量性状基因座方法来识别影响骨骼脆性的染色体区域成为可能。我们假设：1)含有调控大鼠股骨和脊椎脆性、骨密度和几何形状的基因的染色体区域可以被确定；2)骨骼脆性、骨密度和几何形状至少部分由不同的遗传位点调控；以及3)Fischer 344和Lewis大鼠的骨骼生物学不同。我们建议对调节Fischer和Lewis大鼠的骨密度(BMD)、脆性和几何形状的基因进行研究。费舍尔344和刘易斯祖鼠将交配，它们的F1杂交后代将产生一个包含500-600只个体的F2群体。这些大鼠将根据骨密度(目标1)、生物力学特性(目标2)或骨骼几何学(目标3)进行表型。将进行数量性状座位(QTL)分析，以确定影响骨骼表型变异的遗传座位。此外，我们还将进一步研究Fischer和Lewis大鼠品系的特征，以确定a)两个品系的骨骼重建率是否不同，b)它们的骨骼对卵巢切除的反应是否不同，以及c)它们的骨骼对机械负荷的反应是否不同。

There is currently considerable interest in the genetics of osteoporosis. One tool in genetic studies is the inbred rat model. We have identified an inbred strain of rats (Fischer 344) that has lower bone mineral density (BMD) and more fragile bones than several other rat strains. Compared to Lewis rats, adult, female Fischer rats has 12-14% less bone mineral density, 30% more brittleness at the femoral midshaft and 40% less work in fracture in the femur and lumbar vertebra. The Fischer rats are also different than the Lewis rats in femoral and vertebral geometry. Fischer and Lewis strains are among the rat lines screened for microsatellite markers, making it possible to use the quantitative trait loci approach to identify chromosomal regions that affect bone fragility. We hypothesize that 1) chromosomal regions harboring genes that regulate femoral and vertebral fragility, BMD, and geometry can be determined for rats; 2) skeletal fragility, BMD, and geometry are regulated, at least in part, by different genetic loci; and 3) Fischer 344 and Lewis rats are different in their skeletal biology. We propose studies to numerate genes that regulate bone mineral density (BMD), fragility and geometry in Fischer and Lewis rats. Fischer 344 and Lewis progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500- 600 individuals. These rats will be phenotyped based upon BMD (Aim 1), biomechanical properties (Aim 2), or skeletal geometry (Aim 3). Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation in the skeletal phenotypes. In addition we will further characterize the Fischer and Lewis rat strains to determine if a) bone remodeling rates are different in the two strains, b) their bones will respond differently to ovariectomy, and c) their skeletons will respond differently to mechanical loading.