The Influence of PTH during Exercise on Bone Quality

描述（由申请人提供）：预防肌肉骨骼疾病和其他与年龄相关的并发症，如骨质疏松性骨折，依赖于年轻时形成适当的骨量，以保持整个成年期的结构完整性。运动提供了一个独特的组合动态负荷和全身性增加甲状旁腺激素；两种主要形式的刺激与骨形成有关。本奖学金申请中提出的研究重点是了解运动过程中PTH释放对骨适应的影响，通过使用PTH抑制PTH（7-34）或增加PTH的细胞反应来操纵运动过程中PTH的细胞反应（1-34）。核心假说认为运动过程中甲状旁腺激素的释放通过骨细胞活性增强骨的组织力学和骨腔周围基质的适应性。为了验证这一假设，青少年小鼠将在适度运动前接受PTH（7-34）或PTH（1-34）治疗，以改变运动期间细胞对PTH的反应。本研究的第一个目的是确定PTH抑制如何影响骨矿物质含量以及基于力学测试和组织形态学分析的骨的组织水平和结构水平特性。本研究的第二个目的是基于拉曼光谱分析，确定运动和甲状旁腺激素释放对皮质骨组织组成变化的影响，特别是在骨细胞周围的腔旁基质内。同时，基于原位杂交和qRT-PCR技术，也将评估骨细胞间基因表达的变化。使用甲状旁腺激素（7-34）抑制运动过程中甲状旁腺激素全身性变化的细胞反应，将甲状旁腺激素对骨适应的影响与动态负荷所产生的影响分离开来。这项研究的临床意义延伸到发育过程中锻炼的重要性，以提高骨骼质量，降低未来骨折和其他肌肉骨骼并发症（如骨质疏松症）的风险。这项研究的目标将在密歇根大学的一组导师的指导下完成，他们从生物学、化学和工程学方面提供观点。这种跨学科的指导将有助于申请人的职业发展，成为F32 Kirschstein/NRSA奖下的独立研究者。

DESCRIPTION (provided by applicant): Prevention of musculoskeletal diseases and other age-related complications, such as osteoporotic fractures, is dependent on developing proper bone mass at a young age in order to maintain the structural integrity throughout adulthood. Exercise provides a unique combination of dynamic loading and a systemic increase in PTH; two dominate forms of stimuli involved with bone formation. The research proposed in this fellowship application is focused on understanding the influence of PTH release during exercise on bone adaptation by the novel approach of manipulating the cellular response to PTH during exercise by inhibiting it with PTH(7-34) or increasing the cellular response with PTH(1-34). The central hypothesis states that PTH release during exercise enhances the tissue mechanics of bone and adaptation in the perilacunar matrix through osteocyte activity. To test this hypothesis, adolescent mice will be treated with PTH(7-34) or PTH(1-34) prior to moderate exercise to modify the cellular response to PTH during exercise. The first aim of this study will determine how PTH inhibition affects bone mineral content along with the tissue-level and structural-level properties of bone based on mechanical testing and histomorphometry analysis. The second aim of this study will identify the influence of exercise and the role of PTH release, on changes in tissue composition of cortical bone, specifically within the perilacunar matrix surrounding osteocytes, based on Raman spectroscopy analysis. In parallel, changes in gene expression among osteocytes will also be evaluated based on in-situ hybridization and qRT-PCR techniques. The use of PTH(7-34) to inhibit the cellular response to systemic changes in PTH during exercise will uncouple the influence of PTH on bone adaption from that incurred by dynamic loading. The clinical implications of this study extend to the importance of exercise during development to enhance bone quality and reduce the risk of future fracture among other musculoskeletal complications, such as osteoporosis. The goals of this study will be accomplished under the guidance of a team of mentors at the University of Michigan, who provide perspectives from biology, chemistry, and engineering. This interdisciplinary mentorship will contribute to the career development of the applicant to becoming an independent investigator under the F32 Kirschstein/NRSA award.