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。这种组合导致不稳定、易跌倒，从而导致骨折、发病和过早死亡。目前尚不清楚是一种情况先于另一种情况，还是两种情况相互关联。骨骼肌与骨相互作用的传统观点是，骨骼肌承载骨，骨为肌肉提供附着点。从力学角度来看，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，肌肉萎缩本身并不能完全解释骨质疏松症的全部原因，反过来，与衰老相关的骨量减少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和肌肉之间的串扰中起作用。这个项目的假设是在肌肉和骨骼之间有一个内分泌循环，通过每个组织产生的系统因子，这些系统因子是其他组织功能的关键调节因子。骨细胞对肌肉作用的机械负荷的反应是由这些肌肉分泌因子修饰的。反过来，骨细胞通过Wnt/ β -连环蛋白通路调节成骨细胞和肌肉细胞的功能。提出了一系列的实验来研究骨细胞在肌-骨串扰中的作用以及随着年龄的增长所发生的变化。具体目标是1)。确定随年龄增长肌肉对成骨细胞/骨细胞功能的影响2)。确定骨细胞随年龄增长对肌肉质量和功能的影响，3)。4)研究骨细胞对成骨细胞功能的调节，以及这种调节是如何受到肌-骨串扰的调节或影响的。确定机械负荷对骨细胞调节肌肉质量和衰老功能的影响。该项目在概念、初步数据、方法、工具、跨学科和研究人员队伍等方面具有创新性。这些实验的结果应该导致预防和治疗骨质疏松症和肌肉减少症的新疗法。

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. PUBLIC HEALTH RELEVANCE: The traditional view of the muscle-bone relationship is that muscle functions to apply load to the skeleton and bone provides an attachment site for skeletal muscle. Our data suggests that soluble factors from bone cells including osteocytes within their lacunocanalicular network can target muscle. Basic understanding of how bone cells respond to mechanical load and the cross-talk with associated muscles will help to define therapeutic strategies for combating changes in skeletal microarchitecture and muscle weakness. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE; LYNDA F. BONEWALD, CORE LEADER (CL) DESCRIPTION (provided by applicant): The main objective of the Administrative Core is to provide leadership, coordination of effort, statistical advice, managerial support, and facilitatio for the overall operation of the program project grant. The program project grant will be under the directorship of Dr. Lynda F. Bonewald and Co-Director, Dr. Mark Johnson. Dr. Bonewald has been the director of a very successful program project entitled "Osteocyte Function and Response to Mechanical Loading" for 11 years and therefore has the skills and experience to insure the success of this application. The specific aims of this core are: 1).To provide leadership, management, and statistical skills necessary to coordinate and to experimentally design the activities of the program. 2). To coordinate and schedule the activities of the Internal and External Advisory Boards, the PIs meetings, and any support consultants. 3). To coordinate scientific presentations locally and at national and international meetings. 4). To provide for the development and education of students and postdoctoral fellows involved in the program including seminars and data meetings. 5). To provide staff support in the form of budgetary support and review, preparation of grant reports, written communications, manuscripts, and other supportive activities. The program project will contain four subprojects, an administrative core and two support cores, the Muscle/Bone Phenotyping Core and the Transgenic and Mechanical Loading Core. The Director, Co-Director, Principal Investigators and Core Directors will meet with the Internal Advisory Council at least twice a year and with the External Advisory Board once a year. This core will insure the success of each subproject and core. PUBLIC HEALTH RELEVANCE: The inclusion of this Administrative Core is necessary to insure the success of the program project. This program project focuses on a devastating medical problem that increases with age, that of osteoporosis and aging sarcopenia, which usually occur concurrently. The proposed subprojects are novel, innovative and relevant to this issue and should provide insight and means to either prevent or treat these conditions.