GENETICS OF TRABECULAR BONE RESISTANCE TO FRACTURE IN VERTEBRAE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。骨质疏松症是一种与年龄有关的健康问题，其特点是骨骼脆弱，易骨折。目前仅在美国就有4360万人的健康受到骨质疏松症或低骨量的威胁。随着美国人口的老龄化，骨质疏松性骨折的发病率预计会增加，由此带来的个人痛苦和公共卫生成本促使人们深入研究导致这种痛苦和衰弱状况的因素。骨质疏松症是一种复杂的疾病，由许多影响骨量和结构的遗传和环境因素引起，反过来，骨骼对骨折的抵抗力也受到影响。脊柱骨折（即椎体压缩性骨折）是最常见的骨质疏松相关骨折类型，在每年150万例骨质疏松骨折中占近一半。直到最近，对骨骼抗骨折性的研究主要集中在骨量上，骨量是骨骼中骨骼数量的衡量标准。然而，研究表明，很大程度上骨质疏松症的骨折风险与骨量无关。这促使研究人员将骨质疏松症骨折风险的研究扩展到其他测量骨质量的方法，包括直接测量骨脆性。这些指标被称为机械性能，用来评估骨骼作为结构材料的性能。椎骨的机械性能与骨质疏松相关的脊柱压缩性骨折的风险直接相关，因为它们提供了骨骼承受机械负荷而不受损（骨折）的能力的信息。遗传对机械性能的影响已在啮齿动物模型中得到证实，但尚未在灵长类动物（包括人类）中得到证实，也没有研究影响的大小(基因加性效应的方差比例（遗传性（h2））。这里描述的研究是一个试点项目，以验证狒狒作为人类脊椎力学特性的模型。将评估这些特性（即极限力、刚度、功到失效、极限应力、弹性模量和韧性）的正常变化，包括年龄和性别影响，并将其与人类状况进行比较。这些机械特性的遗传性也将被评估。本项目需要验证的具体假设如下：H1：狒狒为研究人类椎体抗骨折性提供了合适的动物模型，显示出与人类相似的椎体力学特性以及年龄和性别对这些特性的影响。H2：脊椎力学特性在狒狒中具有显著的遗传性。利用从250只纯种成年狒狒的第三腰椎（L-3）收集的数据，本项目的具体目标是：1)表征狒狒椎体力学性能的正常变异，包括年龄和性别影响；2)检测和量化这些特性中由基因加性效应引起的变异比例。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Osteoporosis, characterized by bone fragility and increased susceptibility to fracture, is an age-related health problem of immediate public health concern. The well being of 43.6 million people in the U.S. alone is currently threatened by osteoporosis or low bone mass. Individual suffering and public health costs resulting from the projected increase in osteoporotic fracture incidence as the U.S. population ages are motivating intensive research into the factors contributing to this painful and debilitating condition. Osteoporosis is a complex disease resulting from a number of genetic and environmental factors affecting bone mass and architecture, and, in turn, bone¿s resistance to fracture. Fractures of the spine (i.e. compression fractures of the vertebral body) are the most common type of osteoporosis-related fracture, accounting for nearly half of the 1.5 million fractures annually attributed to osteoporosis. Until recently, research into bone¿s resistance to fracture has focused largely on bone mass, a measure of the amount of bone in the skeleton. Studies show, however, that a great deal of osteoporosis fracture risk is independent of bone mass. This has prompted researchers to expand their investigations of osteoporosis fracture risk to other measures of bone quality, including direct measures of bone fragility. These measures, called mechanical properties, assess bone as a structural material. Mechanical properties of the vertebrae are directly related to risk of osteoporosis-related spinal compression fractures as they provide information about bone¿s ability to withstand mechanical loading without being compromised (fractured). A genetic effect on mechanical properties has been demonstrated in the rodent model, but has not been confirmed in primates (including humans), nor has the magnitude of the effect (that proportion of the variance due to the additive effects of genes (heritability (h2)) been investigated. The research described here is a pilot project to validate the baboon as a model for human vertebral mechanical properties. Normal variation in these properties (i.e. ultimate force, stiffness, work to failure, ultimate stress, elastic modulus, and toughness) will be assessed, including age and sex effects, and compared to the human condition. Heritability of these mechanical properties will also be assessed. The specific hypotheses to be tested in this project are as follows: H1: The baboon provides an appropriate animal model for studies of vertebral fracture resistance in humans, showing vertebral mechanical properties, and age and sex effects on these properties, that are similar to those of humans. H2: Vertebral mechanical properties are significantly heritable in the baboon. Using data collected from the 3rd lumbar vertebra (L-3) of 250 pedigreed adult baboons, the specific aims of this project are to: 1) characterize normal variation, including age and sex effects, on vertebral mechanical properties in the baboon, and 2) detect and quantify the proportion of variation in these properties that is due to the additive effects of genes.