Genetic Analysis of Bone Structure and Strength

描述（由申请人提供）：从遗传学角度来看，骨质疏松症是一种复杂的疾病。骨量和结构是高度遗传的特征，但可能有许多基因有助于这些特征。我们在B6 C3 F2小鼠中鉴定了与骨结构和强度相关的数量性状基因座（QTL）。此外，我们已经开发了11个同类系小鼠，其中每一个都包含一个骨结构/强度QTL。我们的初步研究表明，祖小鼠品系（C57 BL/6和C3 H/He）在其骨骼对机械负荷的反应有很大的不同。此外，我们在同类小鼠系B6.C3H-4 T中证明了对机械负荷的骨骼反应性显著增强。与B6对照股骨相比，B6.C3H-4 T股骨的横截面尺寸明显更大，这并不奇怪。这一发现表明，同源小鼠可用于鉴定影响骨细胞力学传导的基因。我们已经确定了四个同类小鼠品系（除了B6.C3H-4 T），改变了股骨横截面的大小。我们建议，以确定这些同源线不同的骨骼机械负荷反应。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小鼠亚系，对每个QTL区域进行遗传解剖，以更好地确定染色体上与股骨BMD和/或结构/强度表型相关的位置。此外，我们将研究从同类系小鼠分离的成骨细胞，以确定其对机械刺激的反应，我们将研究从同类系小鼠骨骼和分离的成骨细胞中的基因表达谱，以确定同类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.