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.
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.
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.
|Johnson, Mark L (2016) How rare bone diseases have informed our knowledge of complex diseases. Bonekey Rep 5:839|
|Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73|
|Gorski, Jeff P; Huffman, Nichole T; Vallejo, Julian et al. (2016) Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age. J Biol Chem 291:4308-22|
|Duan, Peipei; Bonewald, L F (2016) The role of the wnt/Î²-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 77:23-9|
|Maurel, Delphine B; Duan, Peipei; Farr, Joshua et al. (2016) Beta-Catenin Haplo Insufficient Male Mice Do Not Lose Bone in Response to Hindlimb Unloading. PLoS One 11:e0158381|
|Brotto, Marco; Bonewald, Lynda (2015) Bone and muscle: Interactions beyond mechanical. Bone 80:109-14|
|Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning et al. (2015) Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms. PLoS One 10:e0125731|
|Lara-Castillo, N; Kim-Weroha, N A; Kamel, M A et al. (2015) In vivo mechanical loading rapidly activates Î²-catenin signaling in osteocytes through a prostaglandin mediated mechanism. Bone 76:58-66|
|Johnson, Mark L (2015) Unlocking the sost gene. J Bone Miner Res 30:397-9|
|Mo, Chenglin; Zhao, Ruonan; Vallejo, Julian et al. (2015) Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation. Cell Cycle 14:1507-16|
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