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。 公共卫生相关性：对肌肉-骨骼关系的传统观点认为，肌肉的功能是将负荷施加到骨骼上，而骨骼为骨骼肌提供了一个附着点。我们的数据表明，来自骨细胞的可溶性因子，包括其腔隙神经网络中的骨细胞，可以靶向肌肉。对骨细胞如何对机械负荷作出反应以及与相关肌肉的相互作用的基本了解将有助于确定对抗骨骼微结构变化和肌肉无力的治疗策略。 对计划项目的各个组成部分进行评审 核心A：行政核心；Lynda F.Bonewald，核心领导(CL) 描述(由申请人提供)：行政核心的主要目标是为计划项目赠款的整体运作提供领导、工作协调、统计建议、管理支持和便利。该计划项目赠款将由Lynda F.Bonewald博士和联席主任Mark Johnson博士担任董事。11年来，伯恩沃尔德博士一直担任一个非常成功的项目“骨细胞功能和对机械负荷的反应”项目的负责人，因此他拥有确保这一应用成功的技能和经验。这个核心的具体目标是：1)提供必要的领导、管理和统计技能，以协调和试验性地设计该计划的活动。2)。协调和安排内部的活动 和外部咨询委员会、绩效指标会议和任何支助顾问。3)。协调在当地以及在国家和国际会议上的科学陈述。4)。以规定 参与该项目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)。以预算支持和审查、编写赠款报告、书面通信、手稿和其他支持性活动的形式提供工作人员支助。该方案项目将包括四个子项目，一个行政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、联席主任、首席调查员和核心主任每年至少与内部咨询委员会会晤两次，与外部咨询委员会每年会晤一次。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：为了确保计划项目的成功，有必要纳入这一管理核心。这个项目的重点是随着年龄的增长而增加的破坏性医学问题，骨质疏松症和老年性骨质疏松症，这两个问题通常同时发生。拟议的次级项目具有新颖性、创新性和与这一问题相关，应提供预防或治疗这些情况的洞察力和手段。

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.