NEURAL REGULATION OF BONE REMODELING

描述（由申请人提供）：骨质疏松症是一种以低骨量和微结构完整性丧失为特征的骨病，导致骨脆弱性增加和骨折风险。这种疾病的治疗在增加骨密度和降低骨折风险方面仅部分有效。需要进一步的工作来确定控制骨重塑的分子信号，并确定导致骨质疏松症的无数过程如何调节这些信号。有证据表明，感觉神经元信号可以影响骨代谢，这种信号的丧失可能导致骨质疏松症的发生。本研究将利用免疫组织化学和实时PCR技术鉴定骨神经和骨细胞中的感觉神经递质及其受体。骨细胞功能的感觉递质调节将在体外确定。一种体内方法是全身给药感觉神经递质受体拮抗剂，并通过直接局部输注到大鼠胫骨近端，以确定这些递质的内源性释放是否需要维持骨完整性。其他实验将测量骨质疏松大鼠骨神经递质表达和含量的变化，包括一个远程骨质疏松模型，在该模型中，对侧后肢在单侧感觉损伤或后肢固定后失去骨量、强度和神经肽含量。在这些骨质疏松模型中下调的候选神经递质将被直接注入骨质疏松大鼠的胫骨，试图逆转骨质流失并增加骨强度。另一项研究将确定慢性鞘内NGF是否能恢复骨中的神经肽水平并逆转骨质疏松症。预计该项目将；1)鉴定能够在体外调节骨细胞增殖、分化和活性的感觉神经递质，2)证明这些递质及其受体存在于骨中，3)验证它们是保存体内骨骼完整性所必需的，4)确定这些递质在背根神经节切除术和固定化后在骨中被耗尽。5)证明这些递质的恢复可以逆转神经损伤和固定的局部和远程骨质疏松效应。这些研究将有助于识别调节骨重塑的感觉递质，并描述它们在骨质疏松症过程中的作用。

DESCRIPTION (provided by applicant): 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. This proposal will use immunohistochemistry and real time PCR 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 hindlimb loses bone mass, strength, and neuropeptide content after unilateral sensory lesioning or hindlimb immobilization. Neurotransmitter candidates that are down regulated 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. 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.