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。 公共卫生相关性：传统的观点认为，肌肉的功能是向骨骼施加负荷，骨骼为骨骼肌提供附着部位。我们的数据表明，骨细胞（包括骨细胞）的可溶性因子可以靶向肌肉。对骨细胞如何响应机械负荷以及与相关肌肉的串扰的基本理解将有助于确定对抗骨骼微结构和肌无力变化的治疗策略。 审查可持续发展项目的各个组成部分 核心A：行政核心; BONEWALD，核心负责人（CL） 描述（由申请人提供）：行政核心的主要目标是提供领导，协调工作，统计咨询，管理支持和促进计划项目赠款的整体运作。该计划的项目赠款将根据博士林达F。Bonewald和联合主任Mark约翰逊博士。Bonewald博士担任一个非常成功的项目“骨细胞功能和对机械载荷的反应”的主任已有11年，因此拥有确保该应用成功的技能和经验。该核心的具体目标是：1）.提供必要的领导，管理和统计技能，以协调和实验性地设计该计划的活动。2）。协调和安排内部活动 和外部咨询委员会、PI会议以及任何支持顾问。3）。协调在当地以及国家和国际会议上的科学报告。4）。以提供 参与该计划的学生和博士后研究员的发展和教育，包括研讨会和数据会议。5）。以预算支助和审查、编写赠款报告、书面通信、手稿和其他支助活动的形式提供工作人员支助。该计划项目将包括四个子项目，一个管理核心和两个支持核心，肌肉/骨骼表型核心和转基因和机械加载核心。主任、共同主任、主要调查员和核心主任每年至少与内部咨询理事会举行两次会议，与外部咨询委员会举行一次会议。这一核心将确保 每个子项目和核心项目的成功。 公共卫生相关性：纳入这一行政核心是确保方案项目成功的必要条件。这个项目的重点是一个毁灭性的医疗问题，随着年龄的增长，骨质疏松症和老年肌肉减少症，这通常同时发生。拟议的次级项目是新颖的、创新的，与这一问题相关，应提供预防或治疗这些疾病的见解和手段。

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.