Brief Rest-Intervals Amplify the Response of Bone to Mechanical Loading

描述（由申请人提供）：本项目的主要目标是优化零载荷休息时间的能力，以极大地放大骨对机械载荷的反应。我们在以前的NIH资助项目中确定并开发了这种新的标准循环载荷修改。我们的数据表明，每个载荷循环之间的短暂休息间隔有助于降低启动骨膜骨形成所需的应变量，并减少骨对重复机械载荷的适应。在这个项目中，我们假设休息插入负载的成骨效益可以得到优化，因为短暂的休息间隔急性增强和维持Ca 2 +/NFAT介导的基因和蛋白质的调控相比，重复的循环负载。为了探索这一普遍假设，我们将使用综合的多学科方法（体内机械负荷、RT-PCR、免疫组织化学、组织形态计量学和一种新的基于硅试剂的骨细胞动力学模型）来研究三个S。目标。在这些S。我们的目标是：1）确定将最大程度地增强骨膜骨形成的休息间隔持续时间、负荷天数和循环次数的最佳组合，2）确定在单次和多次休息插入或循环负荷后骨细胞基因调节的急性改变，和3）进行一系列体内验证实验，最终尝试使用优化的剩余物，在我们的体内模型中，插入加载干预以将骨膜骨形成靶向到新的皮质部位。如果我们能够充分理解rest插入负载的潜在信号通路，以便我们能够优化和靶向局灶性骨膜骨形成，我们相信，然后启动临床试验以在人类中测试这种策略是合适的。从生物学的角度来看，我们相信所提出的研究将揭示新的见解的mechanotransductionpathways休息插入负载获得其实质性的好处。公共卫生相关性：该项目的重点是实验优化和机械探索细胞信号通路的基础上，令人惊讶的有效性，零负荷休息时间，在提高骨的反应，机械负荷。从临床角度来看，该项目的成功将提高将这一概念转化为骨丢失病理学的非侵入性、非药物干预的潜力。

DESCRIPTION (provided by applicant): The broad goal of this project is to optimize the ability of zero load rest-intervals to greatly magnify the response of bone to mechanical loading. We identified and developed this novel modification of standard cyclic loading during a previous NIH funded project. Our data indicate that brief rest-intervals between each load cycle serve to lower the magnitude of strain required to initiate periosteal bone formation and diminish the accommodation of bone to repetitive bouts of mechanical loading. In this project, we hypothesize that the osteogenic benefit of rest-inserted loading can be optimized because brief rest-intervals acutely enhance and sustain Ca2+/NFAT mediated gene and protein regulation compared with repetitive cyclic loading. To explore this general hypothesis, we will use an integrated multi-disciplinary approach (in vivo mechanical loading, RT- PCR, immunohistochemistry, histomorphometry, and a novel in silica agent based model of bone cell dynamics) to pursue three S. Aims. In these S. Aims, we will: 1) define an optimal combination of rest-interval duration, days of loading, and cycle number that will maximally enhance periosteal bone formation, 2) define acute alterations in bone cell gene regulation following single bout and multiple bouts of rest-inserted or cyclic loading, and 3) perform a series of in vivo validation experiments that will culminate with an attempt to use an optimized rest-inserted loading intervention to target periosteal bone formation to novel cortical sites in our in vivo model. If we are able to sufficiently understand the underlying signaling pathways of rest-inserted loading such that we are able to optimize and target focal periosteal bone formation, we believe it would then be appropriate to initiate a clinical trial to test this strategy in humans. From a biological perspective, we believe the proposed studies will reveal new insights into the mechanotransduction pathways by which rest-inserted loading derives its substantial benefits. PUBLIC HEALTH RELEVANCE: This project is focused on experimentally optimizing and mechanistically exploring the cellular signaling pathways underlying the surprising effectiveness of zero load rest-intervals in enhancing the response of bone to mechanical loading. From a clinical perspective, success in this project would improve the potential to translate this concept into a non-invasive, non-pharmacologic intervention for bone loss pathologies.