NEURAL REGULATION OF BONE REMODELING

描述(申请人提供)：骨质疏松症是一种以骨量减少和微结构完整性丧失为特征的骨骼疾病，导致骨脆性增加和骨折风险增加。这种疾病的治疗在增加骨密度和降低骨折风险方面只有部分效果。需要进一步的工作来确定控制骨重建的分子信号，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，该信号的丢失可能有助于骨质疏松症的发展。这项提议将使用免疫组织化学和实时聚合酶链式反应来识别听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。体内的方法是系统地给予感觉神经递质受体拮抗剂，并通过直接向大鼠胫骨近端局部输注来确定这些递质的内源性释放是否是维持骨骼完整性所必需的。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，包括远程骨质疏松症模型，在该模型中，在单侧感觉受损或后肢制动后，对侧后肢失去骨量、强度和神经肽含量。在这些骨质疏松症模型中下调的候选神经递质随后将直接注入骨质疏松症大鼠的胫骨中，试图逆转骨丢失和增加骨强度。另一项研究将是确定长期鞘内注射NGF是否可以恢复骨骼中的神经肽水平并逆转骨质疏松症。预计该项目将：1)确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骼中，3)证实它们是在体内保持骨骼完整性所必需的，4)确定这些递质在背根节切除和固定后在骨骼中耗尽，5)证明这些递质的恢复可以逆转神经损伤和制动所造成的局部和远程骨质疏松的影响。这些研究将有助于识别调节骨重建的感觉递质，并确定它们在骨质疏松过程中的作用。

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.