A BABOON MODEL FOR THE GENETICS OF CORTICAL BONE MATERIAL PROPERTIES

描述（由申请人提供）：直到最近，大多数关于骨折抵抗的研究都集中在骨量上。然而，流行病学研究表明，很大一部分骨折风险与骨量无关。除了年龄和性别的影响外，骨强度的替代测量（例如骨矿物质含量和密度）一致显示出显著的遗传影响。虽然已经在啮齿类动物身上进行了骨材料特性的遗传研究，但还没有在人类或其他灵长类动物身上进行过类似的研究。其他物种和灵长类动物之间骨折特性的巨大差异强调了对骨材料特性遗传学研究中具有良好遗传特征的非人类灵长类动物模型的需求。我们建议研究基因对皮质骨材料特性的贡献，骨质量的直接测量是骨结构完整性的重要方面。这项研究的最终目的是建立狒狒作为人类骨骼材料特性遗传研究的模型。利用从100只纯种成年狒狒右侧股骨收集的数据，该项目的具体目标是：1)确定皮质骨组织特性，包括弹性模量、屈服和极限强度、屈服后行为、断裂韧性和矿化（灰分和显微ct测定的骨矿物质密度），并确定皮质骨密度和矿化（灰分）与皮质骨材料特性的相关性程度；2)表征狒狒皮质骨材料特性的正常变化，包括年龄和性别影响；3)检测和量化由于基因的加性效应而导致的这些特性的变异比例。我们将评估基因对本项目确定的皮质骨特性和其他研究确定的小梁骨材料特性的相对影响程度。证明皮质骨材料的特性是可遗传的，这是未来研究检测、定位和识别影响狒狒这些特性的特定基因的重要一步。狒狒和人类之间的系统发育接近以及由此产生的骨骼生理学和遗传学相似性激发了这些结果将直接与人类相关的信心。该项目符合美国国家关节炎、肌肉骨骼和皮肤疾病研究所的使命，即支持研究关节炎、肌肉骨骼和皮肤疾病的病因、治疗和预防，其目标是建立一种非人类灵长类动物模型，最终，提高对骨材料特性的遗传调控的理解，这将有助于更早地识别骨折风险更高的人（由于骨质疏松相关的骨骼脆弱性），并允许更早地实施预防和治疗策略。骨质疏松症是一种与年龄相关的健康问题，是一个直接的公共卫生问题，每年在美国导致150万例骨折。骨质疏松性骨折的风险很大程度上是由基因决定的。我们建议发展狒狒作为非人类灵长类动物模型的遗传皮质骨脆性在人类。该模型的建立将最终提高对这些材料特性的遗传调控的理解，从而促进更早地识别骨折高风险人群，并允许更早地实施预防和治疗策略。

DESCRIPTION (provided by applicant): Until recently, a majority of studies of bone fracture resistance focused on bone mass. However, epidemiological studies now suggest that a significant proportion of fracture risk is independent of bone mass. In addition to the effects of age and sex, proxy measures of bone strength (e.g. bone mineral content and density) consistently show significant genetic effects. While genetic studies of bone material properties have been conducted in rodents, similar studies have not been done in humans or other primates. Substantial differences in fracture properties between other species and primates underscore the need for a genetically well-characterized non-human primate model for studies of the genetics of bone material properties. We propose to investigate the contribution of genes to cortical bone material properties, direct measures of bone quality that are essential aspects of a bone's structural integrity. The ultimate objective of the proposed study is to establish the baboon as a model for the genetic study of human bone material properties. Using data collected from the right femur of 100 pedigreed adult baboons, the specific aims of this project are to: 1) determine cortical bone tissue properties including elastic modulus, yield and ultimate strength, post-yield behavior, fracture toughness, and mineralization (ash fraction and microCT-determined bone mineral density) and determine the degree to which cortical bone density and mineralization (ash fraction) are correlated to cortical bone material properties; 2) characterize normal variation, including age and sex effects, on cortical bone material properties in the baboon; and 3) detect and quantify the proportion of variation in these properties that is due to the additive effects of genes. We will assess the relative magnitude of the effect of genes on cortical bone properties as determined in this project vs. trabecular bone material properties determined from other research. Demonstrating that cortical bone material properties are heritable is an essential step leading to future studies to detect, localize, and identify the specific genes that effect these properties in the baboon. Phylogenetic proximity and consequent similarities in skeletal physiology and genetics between baboons and humans inspire confidence that these results will be directly relevant to humans. This project is consistent with the National Institute of Arthritis and Musculoskeletal and Skin Diseases' mission of supporting research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases as the goal is to establish a non-human primate model that will lead, ultimately, to improved understanding of the genetic regulation of bone material properties that will facilitate earlier identification of persons at greater risk for fracture (due to osteoporosis-associated skeletal fragility), and allow earlier implementation of prevention and treatment strategies. Osteoporosis is an age-related health problem of immediate public health concern that results in 1.5 million fractures in the U.S. each year. A great deal of the risk of osteoporotic fracture is due to genes. We propose to develop the baboon as a nonhuman primate model for the genetics of cortical bone fragility in humans. Establishment of this model will lead, ultimately, to improved understanding of the genetic regulation of these material properties, thereby facilitating earlier identification of persons at greater risk for fracture, and allowing for earlier implementation of prevention and treatment strategies.