Osteocyte Regulation of Bone/Muscle with Age

描述（由申请人提供）：骨质疏松症和肌肉减少症是老年人群中的主要临床问题，许多患者同时发生这两种疾病。这种组合导致不稳定性、对福尔斯的易感性，并因此导致骨折、发病和过早死亡。目前还不清楚一个条件是否先于另一个条件，或者这些条件是否有联系。骨骼肌和骨相互作用的传统观点是，腹肌负荷骨，骨为肌肉提供附着部位。力学观点意味着，随着肌肉功能下降，这将导致骨骼负荷减少，因此将导致骨量减少。然而，单独的肌肉萎缩不能完全解释骨质疏松症的全部，而且，与骨质减少相关的衰老也不能完全解释肌肉减少症。我们的初步数据表明，可溶性因子可能在骨骼和肌肉之间的串扰中发挥作用。该计划项目的假设是，肌肉和骨骼之间存在一个内分泌回路，通过每个组织产生系统因子，这些因子是其他组织功能的关键调节因子。这些肌肉分泌的因子改变了骨细胞对肌肉作用的机械负荷的反应。反过来，骨细胞通过Wnt/β-连环蛋白通路的调节剂调节成骨细胞和肌肉细胞的功能。提出了一系列实验来研究骨细胞在肌肉-骨骼串扰中的作用以及随着年龄的增长会发生什么。具体目标是1）。确定肌肉对成骨细胞/骨细胞功能随年龄增长的影响，2）。确定骨细胞对肌肉质量和功能随年龄增长的影响，3）。检查成骨细胞功能随年龄增长的骨细胞调节，以及肌肉-骨骼串扰如何调节或影响这一功能，以及4）。确定机械负荷对骨细胞调节肌肉质量和功能的影响。该项目在概念、初步数据、方法、工具、跨学科性和调查人员干部方面具有创新性。这些实验的结果应该导致新的治疗方法，用于预防和治疗骨质疏松症和肌肉减少症。

DESCRIPTION (provided by applicant): Osteoporosis and sarcopenia are major clinical problems in the aging population and in many patients these two conditions occur concurrently. This combination results in instability, susceptibility to falls and consequently to fracture, morbidity, and premature death. It is unclear whether one condition precedes the other or if the conditions are linked. The traditional view of skeletal muscle and bone interaction is that skeleta muscle loads bone and bone provides an attachment site for muscle. The mechanical perspective implies that as muscle function declines, this would result in decreased loading of the skeleton and therefore would result in a decrease in bone mass. However, muscle atrophy alone cannot fully explain the totality of osteoporosis and, reciprocally, aging associated decreases in bone mass do not fully explain sarcopenia. Our preliminary data suggest that soluble factors may play a role in crosstalk between bone and muscle. The hypothesis for the Program Project is that there is an endocrine loop between muscle and bone through the production of systemic factors by each tissue that are critical regulatory factors for function in the other tissue. The osteocyte response to mechanical loading by the action of muscles is modified by these muscle secreted factors. In turn, the osteocyte regulates both osteoblast and muscle cell function through modulators of the Wnt/beta-catenin pathway. A series of experiments to examine the role of the osteocyte in muscle-bone crosstalk and what happens with aging are proposed. The specific aims are 1). Determine the effects of muscle on osteoblast/osteocyte function with aging, 2). Determine the effects of osteocytes on muscle mass and function with aging, 3). Examine osteocyte regulation of osteoblast function with aging and how this is regulated or influenced by muscle-bone crosstalk, and 4). Determine the effects of mechanical loading on osteocyte regulation of muscle mass and function with aging. This program project is innovative in concept, preliminary data, approach, tools, interdisciplinarity, and cadre of investigators. The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia.