GENETIC ANALYSIS OF BONE STRENGTH IN MICE

描述（由申请人提供）：骨质疏松症是一种复杂的疾病，其特征是骨强度降低和对低创伤骨折的易感性增加。虽然骨质疏松症和骨折的基因贡献很大，但赋予风险的基因和等位基因变异在很大程度上仍不确定。虽然骨密度表型一直是骨质疏松症的大多数遗传分析的焦点，但越来越多的人认识到BMO可能不是骨骼脆弱性的最佳替代指标。 工程原理预测，组织材料特性（骨质量）和骨的形状和大小（几何形状）是骨强度的重要决定因素。骨强度不能在人体内直接测量，但可以在信息丰富的小鼠群体中进行详细的生物力学研究。初步研究已经使我们找到了11个影响小鼠整个股骨强度的染色体位置。这些区域中的六个与弯曲平面中骨的大小、形状和分布密切相关，反映了几何形状对骨强度的重要贡献。然而，其余5个基因座与几何形状没有任何关联，表明这些区域内的基因通过对骨质量施加影响来影响全骨强度。 探索和识别骨骼内在物质特性的遗传决定因素的机会代表了骨骼研究的一个全新领域。我们相信，我们的小组是独特的定位，使在骨骼遗传学这一未开发的领域作出重大贡献。我们有必要的小鼠种群，实验技术到位，最重要的是，我们已经证明，我们的研究策略将成功地识别相关的候选基因。 我们的建议，精细定位股骨骨质量基因，并开发独特的遗传动物模型，以隔离这些基因的影响，提供了一个重要的途径，以确定潜在的基因。这些动物模型中的发现可以用来确定候选基因或途径，以进行更有针对性的人类研究。最佳骨质量所必需的基因的发现将提供巨大的洞察力，了解一个鲜为人知的，但至关重要的整体骨强度的组成部分。

DESCRIPTION (provided by applicant): Osteoporosis is a complex disease characterized by reduced bone strength and increased susceptibility to low trauma fracture. Although a strong genetic contribution to osteoporosis and fracture is well-documented, the genes and allelic variants conferring risk remain largely undefined. While the BMD phenotype has been the focus of most genetic analyses of osteoporosis, there is increasing recognition that BMO may not be the best surrogate measure for skeletal fragility. Engineering principles predict that tissue material properties (bone quality) and the shape and size of bone (geometry) are important determinants of bone strength. Bone strength cannot be directly measured in vivo in humans, but detailed biomechanical studies can be performed in informative mouse populations. Preliminary studies have led us to 11 chromosomal locations that influence whole femoral bone strength in the mouse. Six of these regions are strongly associated with the size, shape and distribution of bone in the plane of bending reflecting the important contribution of geometry to bone strength. However, the remaining 5 loci are devoid of any association with geometry suggesting that genes residing within these regions impact whole bone strength by exerting effects on bone quality. The opportunity to explore and identify the genetic determinants of the intrinsic material properties of bone represents an entirely new realm of skeletal inquiry. We believe that our group is uniquely positioned to make a major contribution in this unexplored field of skeletal genetics. We have the necessary mouse populations available, the experimental techniques in place, and most importantly we have demonstrated that our research strategy will successfully identify relevant candidate genes. Our proposal to fine map femoral bone quality genes and develop unique genetic animal models for isolating the effects of those genes offers an important route to the identification of the underlying genes. Findings in these animal models can then be used to pinpoint candidate genes or pathways for more focused human investigation. Discovery of the genes essential for optimal bone quality would offer tremendous insight into a poorly understood, but critically important component of overall bone strength.