A BABOON MODEL FOR THE GENETICS OF CORTICAL BONE MATERIAL PROPERTIES

描述(由申请人提供)：直到最近，大多数关于骨断裂抗性的研究都集中在骨量上。然而，现在的流行病学研究表明，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)一直显示出显著的遗传效应。虽然已经在啮齿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中进行类似的研究。其他物种和灵长类动物之间骨折特性的显著差异突出表明，需要一个具有良好遗传学特征的非人类灵长类动物模型来研究骨材料特性的遗传学。我们建议调查基因对皮质骨材料特性的贡献，这是骨质量的直接测量，是骨结构完整性的基本方面。这项拟议研究的最终目标是建立一个用于人类骨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，包括弹性模数、屈服和极限强度、屈服后行为、断裂韧性和矿化(灰分和microCT确定的骨密度)，并确定皮质骨密度和矿化(灰分)与皮质骨材料特性的关联程度；2)表征包括年龄和性别在内的正常变异对狒狒皮质骨材料特性的影响；以及3)检测并量化由于基因的相加效应而导致这些特性变化的比例。我们将评估基因对皮质骨特性的影响的相对大小，如本项目所确定的与其他研究确定的骨小梁材料特性之间的关系。证明皮质骨材料的属性是可遗传的，这是导致未来研究发现、定位和识别影响狒狒这些属性的特定基因的关键一步。在系统发育上的接近，以及随后在骨骼生理学和遗传学上的相似之处，让人们相信这些结果将与人类直接相关。该项目与国家关节炎和肌肉骨骼及皮肤疾病研究所的使命一致，即支持对关节炎、肌肉骨骼和皮肤疾病的病因、治疗和预防的研究，其目标是建立一个非人类灵长类动物模型，最终将导致更好地了解骨材料特性的遗传调节，从而有助于更早地识别(由于骨质疏松症相关的骨骼脆性)骨折风险较高的人，并使预防和治疗策略能够更早地实施。骨质疏松症是一个与年龄相关的健康问题，直接关系到公共卫生，每年在美国导致150万人骨折。骨质疏松性骨折的风险很大程度上是由基因造成的。我们建议开发一种非人类灵长类动物模型，用于研究人类皮质骨脆性的遗传学。这一模型的建立最终将有助于更好地理解这些材料特性的遗传调控，从而有助于更早地识别有较大骨折风险的人，并使预防和治疗战略能够更早地实施。

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.