Principal Investigator: Wade S. Kingery, MD Co-Investigators: Christopher R. Jacobs, PhD and David Clark, MD, PhD Collaborators: David Yeomans, PhD and Steven Wilson, PhD Objectives: Osteoporosis is a bone disease characterized by low bone mass and loss of microarchitectural integrity, leading to increased bone fragility and risk of fracture. Osteoporotic fractures exact a terrible toll on the population with respect to morbidity and cost, and to a lesser extent mortality, which will increase dramatically with the growing elderly population. Osteoporotic fractures are also a serious problem in the spinal cord injury and stroke patient populations. Treatments for this disease are only partially effective at increasing bone density and reducing fracture risk. Further work is needed to define the molecular signals controlling bone remodeling and determining how the myriad processes causing osteoporosis regulate these signals. There is evidence that sensory neuronal signaling can influence bone metabolism and that the loss of this trophic signal might contribute to the development of bone loss and fragility. The objectives of this proposal are; 1) to identify the sensory neuropeptides required for the maintenance of adult skeletal integrity, 2) determine whether common osteoporotic processes are associated with loss of neuropeptide signaling, 3) demonstrate that restoration of neuropeptide signaling can reverse the bone loss and fragility that develop in mouse osteoporosis models. Research Plan: These experiments will use mutant mice lacking genes for sensory neuropeptides to define the effect each specific neurotransmitter has on bone structure and cellular activity. Bone phenotyping will utilize microCT scanning, histomorphometry, biomechanical testing, and biochemical markers of bone metabolism. Immunohistochemistry, enzyme immunoassays, and real time PCR will be used to identify and quantify sensory transmitters and their receptors in osseal nerves and bone cells obtained from mouse osteoporosis models of aging, glucocorticoid use, and estrogen deficiency. A viral vector gene delivery approach will be used to test the hypothesis that facilitated endogenous release of sensory neuropeptides can reverse bone loss and fragility in these mouse osteoporosis models. Work Accomplished: The transgenic mouse colonies are currently being bred at our facility and bone phenotyping has commenced. The aging, glucocorticoid use, and ovariectomy induced osteoporosis models have been developed. The HSV viral vectors for neuropeptide overexpression have been constructed and are now being tested. Expected Outcome: It is anticipated that this project will determine the role sensory transmitters play in the maintenance of skeletal integrity, characterize sensory cell signalloss in osteoporotic processes, and demonstrate the feasibility of a promising new approach for the treatment of osteoporosis, a disease affecting over a half million veterans enrolled in the VA Health Care System. Funding Source: Department of Veterans Affairs - Merit Review
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