Osteocyte Regulation of Bone/Muscle with Age

描述(申请人提供)：骨质疏松症和骨质疏松症是老年人口的主要临床问题，在许多患者中，这两种情况同时发生。这种组合会导致不稳定，容易摔倒，进而导致骨折、发病率和过早死亡。目前尚不清楚一个条件是否在另一个条件之前，或者这些条件是否有关联。传统的骨骼肌与骨骼相互作用的观点认为，骨骼肌承载着骨骼，而骨骼为肌肉提供了连接部位。从力学的角度来看，随着肌肉功能的下降，这将导致骨骼负荷的减少，从而导致骨量的减少。然而，单靠肌肉萎缩不能完全解释骨质疏松症的整体，反过来，与年龄相关的骨量减少也不能完全解释骨质疏松症。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。该项目的假设是，肌肉和骨骼之间存在内分泌循环，通过每个组织产生的系统因子，这些因子是另一个组织功能的关键调节因素。这些肌肉分泌的因子改变了骨细胞对肌肉作用下的机械负荷的反应。反过来，骨细胞通过Wnt/β-catenin途径的调节器来调节成骨细胞和肌肉细胞的功能。我们提出了一系列实验，以检验骨细胞在肌肉-骨骼串扰中的作用，以及随着年龄的增长会发生什么。具体目标有：1)。2)测定肌肉对成骨细胞/骨细胞功能的影响。3)测定骨细胞随年龄增长对肌肉质量和功能的影响。研究随年龄增长的骨细胞对成骨细胞功能的调节，以及肌肉-骨骼串扰是如何调节或影响这一调节的，以及4)。确定机械负荷对骨细胞随年龄增长对肌肉质量和功能的调节的影响。该项目在概念、初步数据、方法、工具、跨学科和调查队伍等方面都具有创新性。这些实验的结果应该会导致预防和治疗骨质疏松症和骨质疏松症的新疗法。

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.