Principal Investigator: Wade S. Kingery, MD Co-Investigators: Christopher R. Jacobs, PhD; Wei Yao, MD, PhD; and Nancy Lane, MD Consultant: Bernard Halloran, 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. 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 signal might contribute to the development of osteoporosis. The primary objectives of this research are; 1) identify the sensory neurotransmitters capable of regulating bone cell function in vitro, 3) identify the sensory neurotransmitters that contribute to the maintenance of bone density, microarchitecture, and strength, and 3) characterize the local and remote osteoporotic effects of sensory differentiation and immobilization, and then determine whether restoration of neuronal signaling can reverse these effects. Research Plan: This proposal will use immunohistochemistry to identify sensory neurotransmitters and their receptors in osseal nerves and bone cells. Sensory transmitter modulation of bone cell functions will be determined in vitro. An in vivo approach will be to administer sensory neurotransmitter receptor antagonists systemically and by direct local infusion into the proximal tibia of rats to establish whether the endogenous release of these transmitters is required for the maintenance of bone integrity. Additional experiments will measure changes in bone neurotransmitter expression and content in osteoporotic rats, including a remote osteoporosis model in which the contralateral hind limb loses bone mass, strength, and neuropeptide content after unilateral sensory lesioning or hind limb immobilization. Neurotransmitter candidates that are downregulated in these osteoporosis models will then be directly infused into the tibias of osteoporotic rats in an attempt to reverse bone loss and increase bone strength. An additional line of investigation will be to determine whether chronic intrathecal NGF administration can restore neuropeptide levels in bone and reverse osteoporosis. Work Accomplished: This project started in December 2004 and to date we have demonstrated that substance P can stimulate bone marrow stromal cell proliferation and differentiation into osteoblasts. We have also observed that substance P can inhibit the development of TRAP+ multinucleated cells and that substance P receptors are present on bone marrow stromal cells and osteoclast precursor cells. Expected Outcome: It is anticipated that this project will; 1) identify sensory neurotransmitters capable of regulating bone cell proliferation, differentiation, and activity in vitro, 2) demonstrate that these transmitters and their receptors are present in bone, 3) verify that they are required for the preservation of skeletal integrity in vivo, 4) establish that these transmitters are depleted in bone after dorsal root gangliectomy and immobilization, and 5) demonstrate that restoration of these transmitters can reverse the local and remote osteoporotic effects of nerve trauma and immobilization. These investigations will help to identify the sensory transmitters that modulate bone remodeling and characterize their roles in osteoporotic processes. Publications Kingery, W.S., Offley, S,C., Guo, T., Wei, T., Lindsey, D.P., Jacobs, C.R. Immobilization induces a widespread loss of bone integrity and impaired neurohumoral signaling. J Bone Miner Res, 2004, 19 (suppl 1): S438. Offley, S.C., Guo, T.Z., Wei, T., Clark, J.D., Vogel, H., Lindsey, D.P., Jacobs, C.R., Yao, W., Lane, N.E., Kingery, W.S., Capsaicin sensitive sensory neurons contribute to the maintenance of trabecular bone integrity, J Bone Min Res, 2005, 20: 257-267. Wang, L., Zhao, R., Shi, X., Wei, T., Halloran, B.P., Clark, D.J., Jacobs, C.R., Kingery, W.S., Substance P regulates osteogenic activity of mouse bone marrow stromal cells, Submitted. Sabsovich, I., Clark, D.J., Liao, G., Peltz, G., Lindsey, D.P, Jacobs, C.R., Yao, W., Guo, T.Z., Kingery, W.S., Bone microstructure and its associated genetic variability in 12 inbred mouse strains: uCT study and in silico genome scan, Submitted. Funding Source: NIH
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