Interaction of Mechanical Loading and Teriparatide on Bone Mass and Performance

机械负荷和特立帕肽对骨量和性能的相互作用

• 批准号: 9026509
• 负责人: ROBERT Daniel BLANK
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026509
• 关键词: A Mouse; Address; Affect; Age; Animals; Biomechanics; Bone Density; Data; Diaphyses; Distal; Drug Combinations; Drug Interactions; Elderly; Exercise; Failure; Femur; Fracture; Genes; Genetic; Genetic Determinism; Geometry; Goals; Hormones; Immunotherapy; Inbred Strains Mice; Individual; Investigation; Knowledge; Korean War; Lead; Left; Measures; Mechanics; Mediating; Modeling; Mouse Strains; Mus; Mutation; Parathyroid gland; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Physical therapy; Physiological; Population; Porosity; Recombinants; Research; Risk; Site; Skeleton; Spinal cord injury; Stress; Teriparatide; Trauma; Veterans; Vietnam; Weight-Bearing state; Wild Type Mouse; Work; World War II; base; bone; bone mass; cohort; density; design; expectation; experience; fall risk; follow-up; gene environment interaction; high risk; human PTH protein; in vivo; long bone; male; osteogenic; pleiotropism; prevent; programs; public health relevance; response; skeletal; spine bone structure; substantia spongiosa; tibia; trait

Veterans are at high risk for skeletal fragility and fracture. In particular, conditions that limit mobility-and consequently decrease physiologic loading of the skeleton-concomitantly increase fracture risk. Inbred mouse strains are known to differ in their responsiveness to experimentally imposed loading, bone mineral density, and long bone diaphyseal geometry. Loading-induced modeling is known to be enhanced by the action of parathyroid hormone (PTH). However, the uniformity of this effect across genetic backgrounds has not been studied. While recombinant human PTH 1-34 (teriparatide, TPT) leads to dramatic increases in vertebral trabecular bone volume fraction and bone mineral density (BMD), this may occur at the expense of increased cortical porosity and reduced trabecular bone volume fraction at unloaded sites. Finally, animal studies of the interaction of mechanical loading and PTH have focused exclusively on the modeling response, and have largely ignored the potential for increased cortical porosity. There is therefore a lack of data addressing the interaction of PTH and mechanical loading on osteoclastic activity across diverse genetic backgrounds. The objective of this proposal is to compare the effects of TPT, mechanical loading, and their interaction in C57BL/6J (B6) and A/J (A) male mice. The central hypothesis of this project is that genetic background affects not only the response to mechanical loading, but the response to TPT and the interaction between loading and TPT as well, at both experimentally loaded sites and at remote sites. We will subject male A and B6 mice to intermittent cyclic loading of the right tibia over a 3-week period, treating half the mice of each strain with TPT. Using these mice, we will undertake the following specific aims: 1) Measure the mouse strain-specific response to TPT and mechanical loading on cortical modeling, 2) Determine the impact of loading and TPT on cortical bone at unloaded sites, 3) Determine the impact of loading and TPT treatment on trabecular bone. We will use defined loading of the tibia in compression as the experimental approach to accomplish the specific aims. At the conclusion of the proposed studies, we will have determined the interaction of TPT and mechanical loading on cortical bone modeling in A and B6 mice. We will have determined the effects of mechanical loading and TPT on cortical and trabecular bone at sites not subjected to experimental loading in A and B6 mice. These data will provide a comprehensive comparison of the response to TPT, mechanical loading, and their interaction in a pair of mouse strains used in constructing the collaborative cross. They will leave us poised to develop a research program aimed at optimizing the combination of bone anabolic drugs and physical therapy in immobilized patients to prevent low trauma fractures. We expect that this line of investigation will lead to better-informed medication and exercise prescriptions for patients at risk for low trauma fracture, particularly those with limited mobility.

退伍军人骨骼脆弱和骨折的风险很高。特别是，限制 流动性-并因此降低了生理负荷的胰腺-伴随 增加骨折风险。已知近交系小鼠品系在它们对以下物质的反应性方面不同： 实验施加的载荷、骨矿物质密度和长骨骨干几何形状。 负荷诱导的建模是已知的增强的作用甲状旁腺激素 （PTH）。然而，这种效应在不同遗传背景下的一致性尚未得到研究。 虽然重组人PTH 1-34（特立帕肽，TPT）导致脊椎骨肿瘤的急剧增加， 骨小梁体积分数和骨矿物质密度（BMD），这可能会发生在牺牲 增加皮质骨孔隙度和减少松质骨体积分数在卸载网站。 最后，机械负荷和PTH相互作用的动物研究集中在 完全依赖于建模响应，并且在很大程度上忽略了增加 皮层孔隙度因此，缺乏关于PTH和 不同遗传背景下的骨细胞活性的机械负荷。客观 该建议的目的是比较TPT、机械载荷及其相互作用对 C57 BL/6 J（B6）和A/J（A）雄性小鼠。这个项目的核心假设是， 背景不仅影响对机械载荷的响应，而且影响对TPT的响应， 在两个实验加载部位和两个试验加载部位， 远程站点。我们将雄性A和B6小鼠的右胫骨进行间歇性循环负荷 在3周的时间内，用TPT处理每个品系的一半小鼠。利用这些老鼠， 进行以下具体目标：1）测量小鼠品系特异性对TPT的反应 2）确定载荷和TPT对皮质建模的影响， 未加载部位的皮质骨，3）确定加载和TPT治疗对 骨小梁我们将使用规定的胫骨压缩载荷作为实验 实现具体目标的方法。在建议的研究完成后，我们会 已经确定了TPT和机械载荷对A中皮质骨建模的相互作用， B6小鼠我们将确定机械负荷和TPT对皮质的影响， A和B6小鼠中未经受实验负荷的部位的骨小梁。这些 数据将提供对TPT、机械载荷和 它们在用于构建协作杂交的一对小鼠品系中的相互作用。他们将 让我们准备开发一个旨在优化骨骼组合的研究项目， 在固定患者中使用合成代谢药物和物理治疗，以预防低创伤骨折。 我们期望这条调查线将导致更好的知情药物和锻炼 为有低创伤骨折风险的患者，特别是那些行动不便的患者提供处方。