Functionality and Fracture Susceptibility of Corticocancellous Structures

描述(申请人提供)：骨骼是一个复杂的系统，其关键功能是足够僵硬和强大，以支持与日常活动相关的体力。了解遗传和环境变异是如何影响这一功能的，对于充分理解为什么某些人更容易骨折至关重要。骨小梁和皮质特征都有助于皮质松质骨结构的负荷，而这两种组织类型的相对比例的变化是骨折风险的关键决定因素。然而，皮质骨和骨小梁组织的相对比例在个体之间的差异的原因还不是很清楚。基于我们自己对小鼠和人类长骨功能关系的研究，我们假设，皮质和骨小梁特征的差异源于功能适应(沃尔夫定律)和影响骨大小的遗传变量之间的相互作用。我们建议确定影响椎体大小的遗传变异是如何通过皮质和骨小梁特征之间的特定功能相互作用来补偿的，椎体大小是骨折风险的关键决定因素。我们假设，骨小梁质量和结构的遗传变异取决于影响皮质大小和质量的遗传变异所产生的负荷分担程度。此外，我们建议确定皮质和骨小梁特征之间的功能相互作用如何随着年龄的增长保持强度。由于表型协变会导致成人性状的遗传差异，我们也测试了这样的假设，即某些成人性状集将更耐受骨丢失，并能够更好地随着年龄的增长保持力量。我们将使用一组AXB/BXA重组近交系(RI)小鼠品系来检验这些假设，这是一个研究正常(即非病理)遗传变异范围内性状之间补偿关系的强大模型。在目标I中，我们使用通径分析来检验小梁和皮质性状是否显示出补偿关系，并确定补偿影响成人椎体大小的遗传变异的性状交互作用。在AIM II中，我们确定了生长过程中表型协变是如何产生的。在目标III中，我们评估了表型协变对骨细胞随年龄增长保持硬度和强度的能力的影响。最后，我们测试性别如何影响生长和衰老过程中的表型协变。这一系统分析在功能性的背景下考察了性状之间的关系，将为骨折易感性的遗传基础提供新的见解。公共卫生相关性：我们建议确定皮质和骨小梁特征之间的功能相互作用如何补偿影响椎体大小的遗传变异，并促进骨折易感性。我们使用遗传随机的近交系小鼠品系来确定在生长过程中出现的补偿性状交互作用如何导致不同的成体特征集，表现出随着年龄增长而保持力量的不同能力。这一系统分析在功能性的背景下考察了性状之间的关系，将为骨折易感性的遗传基础提供新的见解。

DESCRIPTION (provided by applicant): Bone is a complex system whose critical function is to be sufficiently stiff and strong to support the physical forces associated with daily activities. Understanding how genetic and environmental variants compromise this function is critical to fully understanding why certain individuals are more susceptible to fracturing. Trabecular and cortical traits both contribute to load bearing of corticocancellous structures, and variation in the relative proportion of these two tissue types is a critical determinant of fracture risk. However, the cause of variation in the relative proportion of cortical and trabecular tissues among individuals is not well understood. Based on our own work examining functional relationships in mouse and human long bone, we postulate that variation in cortical and trabecular traits arises from an interplay between functional adaptation (Wolff's Law) and genetic variants affecting bone size. We propose to determine how genetic variants affecting vertebral size, a critical determinant of fracture risk, are compensated by specific functional interactions among cortical and trabecular traits. We hypothesize that genetic variation in trabecular bone mass and architecture depends on the degree of load sharing arising from genetic variants affecting cortical size and quality. Further, we propose to determine how the functional interactions among cortical and trabecular traits maintain strength with aging. Because phenotypic covariation gives rise to genetically varying sets of adult traits, we also test the hypothesis that certain adult trait sets will be more resistant to bone loss and better able to maintain strength with aging. We will test these hypotheses using a panel of AXB/BXA Recombinant Inbred (RI) Mouse Strains, which is a powerful model to study compensatory relationships among traits within the normal (i.e., non-pathological) range of genetic variability. In Aim I, we use Path Analysis to test whether trabecular and cortical traits show a compensatory relationship, and identify the trait interactions that compensate for genetic variants affecting adult vertebral size. In Aim II, we determine how phenotypic covariation arises during growth. In Aim III, we assess the impact of phenotypic covariation on the ability of bone cells to maintain stiffness and strength with aging. Finally, we test how sex affects phenotypic covariation throughout growth and aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility. PUBLIC HEALTH RELEVANCE: We propose to determine how functional interactions among cortical and trabecular traits compensate for genetic variants affecting vertebral size and contribute to fracture susceptibility. We use genetically randomized inbred mouse strains to determine how compensatory trait interactions arising during growth lead to varying sets of adult traits expressing different abilities to maintain strength with aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility.