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，取决于在年轻时发展适当的骨量，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增加甲状旁腺素;两个主导形式的刺激参与骨形成。本奖学金申请中提出的研究重点是了解运动期间PTH释放对骨适应的影响，通过使用PTH（7-34）抑制运动期间对PTH的细胞反应或使用PTH（1-34）增加细胞反应来操纵运动期间对PTH的细胞反应的新方法。中心假设指出，PTH释放在运动过程中增强骨组织力学和适应性的骨细胞活动，通过周围的骨基质。为了检验这一假设，将在适度运动之前用PTH（7-34）或PTH（1-34）处理青春期小鼠，以改变运动期间对PTH的细胞反应。本研究的第一个目的是根据力学测试和组织形态计量学分析，确定PTH抑制如何影响骨矿物质含量沿着骨的组织水平和结构水平特性。本研究的第二个目的是根据拉曼光谱分析，确定运动的影响和PTH释放对皮质骨组织成分变化的作用，特别是骨细胞周围的骨关节腔基质。同时，还将基于原位杂交和qRT-PCR技术评价骨细胞中基因表达的变化。使用PTH（7-34）抑制运动期间对PTH的系统性变化的细胞反应将使PTH对骨适应的影响与动态负荷引起的影响分离。这项研究的临床意义延伸到发育过程中锻炼的重要性，以提高骨质量和降低未来骨折的风险，以及其他肌肉骨骼并发症，如骨质疏松症。这项研究的目标将在密歇根大学的导师团队的指导下完成，他们提供生物学，化学和工程学的观点。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奖下的独立调查员。

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.