Genetic Analysis of Bone Structure and Strength

描述(申请人提供)：从遗传学角度看，骨质疏松症是一种复杂的疾病。骨量和结构是高度可遗传的特征，但可能有许多基因对这些特征起作用。我们在B6C3F2小鼠中发现了与骨骼结构和力量相关的数量性状基因座(QTL)。此外，我们还开发了11个同源小鼠品系，每个品系都包含一个骨结构/强度QTL。我们的初步研究表明，祖系小鼠(C57BL/6和C3H/He)对机械载荷的骨骼反应有很大的不同。此外，我们在同源小鼠系B6.C3H-4T中证明了显著增强的骨骼对机械负荷的反应性。毫不奇怪，与B6对照股骨相比，B6.C3H-4T股骨的横截面尺寸明显更大。这一发现表明，同源基因小鼠可以用来识别影响骨骼中细胞机械转导的基因。我们已经确定了四个同源小鼠系(除了B6.C3H-4T)，它们改变了股骨横截面大小。我们建议确定这些同源基因系中哪些在骨骼机械负荷响应方面不同。然后，我们将开发同源亚系，并完成QTL的精细定位，以分离有助于改变机械转导的基因。我们将开发多个同源基因小鼠亚系，对每个QTL区域进行遗传解剖，以更好地定位影响股骨骨密度和/或结构/强度表型的染色体位置。此外，我们将研究从同源小鼠系分离的成骨细胞，以确定它们对机械刺激的反应性，并将检测同源小鼠骨骼和分离的成骨细胞中的基因表达谱，以确定同源系之间不同的遗传途径。

DESCRIPTION (provided by applicant): Osteoporosis is a complex disease, from a genetics standpoint. Bone mass and structure are highly heritable traits, but there are probably many genes that contribute to these traits. We have identified quantitative trait loci (QTL) in B6C3F2 mice that are linked to bone structure and strength. In addition, we have developed 11 congenic mouse lines, each of which contains a bone structure/strength QTL. Our preliminary studies demonstrate that the progenitor mouse strains (C57BL/6 and C3H/He) differ considerably in their skeletal response to mechanical loading. Furthermore, we demonstrated in a congenic mouse line, B6.C3H-4T, a significantly enhanced skeletal responsiveness to mechanical loading. Not surprisingly, B6.C3H-4T femurs have significantly larger cross-sectional size compared to B6 control femurs. This finding suggests that congenic mice can be used to identify genes that affect cellular mechanotransduction in bone. We have identified four congenic mouse lines (in addition to B6.C3H-4T) that have altered femoral crosssectional size. We propose to determine which of these congenic lines differ in skeletal mechanical loading response. We will then develop congenic sublines and complete fine mapping of the QTLs to isolate genes contributing to altered mechanotransduction. We will develop multiple sublines of congenic mice to genetically dissect each QTL region to better pinpoint the location on the chromosome contributing to femoral BMD and/or structure/strength phenotypes. In addition we will study osteoblasts isolated from congenic mouse lines to determine their responsiveness to mechanical stimuli and we will examine gene expression profiles in bones from congenic mice and in isolated osteoblasts in order to determine the genetic pathways that differ among the congenic lines.