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，对低创伤骨折的易感性增加。尽管骨质疏松症和骨折与基因密切相关已有充分的证据，但致病基因和等位基因变异在很大程度上仍未明确。尽管BMD表型一直是大多数骨质疏松症基因分析的焦点，但人们越来越认识到，BMO可能不是骨骼脆性的最佳替代指标。 工程学原理预测，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。骨强度不能直接在人体内测量，但详细的生物力学研究可以在信息量丰富的小鼠种群中进行。初步研究发现了11个影响小鼠股骨整体强度的染色体位置。其中六个区域与骨在弯曲平面上的大小、形状和分布密切相关，反映了几何学对骨强度的重要贡献。然而，其余5个基因座与几何学没有任何关联，这表明位于这些区域的基因通过影响骨质量来影响整体骨强度。 探索和确定骨骼内在材料特性的遗传决定因素的机会代表着骨骼研究的一个全新领域。我们相信，我们的团队处于独特的地位，可以在这一尚未探索的骨骼遗传学领域做出重大贡献。我们有必要的小鼠种群可用，实验技术到位，最重要的是，我们已经证明了我们的研究战略将成功地识别相关的候选基因。 我们建议对股骨质量基因进行精细定位，并建立分离这些基因影响的独特的遗传动物模型，这为识别潜在基因提供了一条重要的途径。然后，这些动物模型中的发现可以用来精确定位候选基因或途径，以便进行更有针对性的人类研究。对最佳骨骼质量至关重要的基因的发现将为我们提供对整体骨骼强度这一鲜为人知但至关重要的组成部分的巨大洞察力。

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.