NEURAL REGULATION OF BONE REMODELING

骨重塑的神经调节

• 批准号: 7479204
• 负责人: WADE S KINGERY
• 金额: $ 29.92万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479204
• 关键词: Ablation; Afferent Neurons; Bilateral; Bone Density; Bone Diseases; Bone remodeling; Calcitonin Gene-Related Peptide; Caliber; Capsaicin; Cell Proliferation; Cell physiology; Chronic; Clinical; Contralateral; Cultured Cells; Data; Deafferentation procedure; Denervation; Development; Disease; Dual-Energy X-Ray Absorptiometry; Effectiveness of Interventions; Environment; Equipment; Fracture; Funding; Glutamates; Goals; Growth Factor; Hindlimb; Hindlimb Suspension; Homeostasis; Hormones; Immobilization; Immunohistochemistry; In Vitro; Infusion procedures; Investigation; Ipsilateral; Knowledge; Laboratories; Lesion; Limb structure; Localized; Maintenance; Materials Testing; Measures; Mediating; Metabolic Diseases; Methods; Modeling; Molecular; Nerve; Nerve Fibers; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neurons; Neuropeptides; Neurotoxins; Neurotransmitter Receptor; Neurotransmitters; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteoporosis; Patients; Perfusion; Play; Polymerase Chain Reaction; Positioning Attribute; Process; Prostaglandins; Publishing; Range; Rattus; Receptor Activation; Research; Research Personnel; Resource Sharing; Resources; Risk; Role; Role playing therapy; Sensory; Sensory Ganglia; Signal Transduction; Skeletal system; Slice; Somatostatin; Spinal Ganglia; Stromal Cells; Study Section; Substance P; Testing; Tibial Fractures; Time; Tissues; Trauma; Work; afferent nerve; base; bone; bone cell; bone loss; bone metabolism; bone strength; capsaicin receptor; cytokine; expectation; in vivo; innovation; nerve injury; neurophysiology; neuroregulation; neurotrophic factor; novel; pre-clinical; prevent; progenitor; programs; receptor; relating to nervous system; research study; restoration; sciatic nerve; skeletal preservation; spinal nerve posterior root; tibia

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.

描述（由申请人提供）：骨质疏松症是一种骨骼疾病，其特征是骨骼质量低和微构造完整性的丧失，导致骨骼脆弱性增加和骨折风险。该疾病的治疗仅在增加骨密度和降低骨折风险方面有效。需要进一步的工作来定义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，感觉神经元信号传导会影响骨代谢，并且该信号的丧失可能有助于骨质疏松的发展。该建议将使用免疫组织化学和实时PCR来鉴定骨神经和骨细胞中的感觉神经递质及其受体。将在体外确定骨细胞功能的感觉发射器调制。一种体内方法是系统地施用感觉神经递质受体拮抗剂，并直接将局部输注大鼠的近端胫骨，以确定这些发射机的内源性释放是否需要维持骨骼完整性。其他实验将衡量骨质疏松大鼠中骨神经递质表达和含量的变化，包括远程骨质疏松模型，其中对侧后肢在单方面感觉性损伤或后肢固定后，对侧后肢失去骨量，强度和神经肽含量。在这些骨质疏松模型中调节的候选候选者将直接注入骨质疏松大鼠的胫骨，以试图逆转骨质流失并增加骨骼强度。另一项研究将是确定慢性鞘内NGF给药是否可以恢复骨骼和反向骨质疏松症的神经肽水平。预计该项目将； 1）确定能够调节骨细胞增殖，分化和体外活性的感觉神经递质，2）证明，这些发射机及其受体存在于骨骼中，3）证实它们是在体生中保存骨骼完整性所必需的，4）在骨骼中均可散布这些传播者，并在骨骼后均能逐渐消失，并在骨骼后持续延伸，并在骨骼后置于脑肠脑凝结术，并在骨骼中丧失了脑脑脑的持续状态，并确定这些传播物是在骨骼中耗尽的。扭转神经创伤和固定化的局部和远程骨质疏松作用。这些研究将有助于确定调节骨重塑并表征其在骨质疏松过程中的作用的感觉发射器。

项目成果

Bisphosphonates Inhibit Pain, Bone Loss, and Inflammation in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome.

• DOI: 10.1213/ane.0000000000001518
• 发表时间: 2016-10
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Wang L;Guo TZ;Hou S;Wei T;Li WW;Shi X;Clark JD;Kingery WS
• 通讯作者: Kingery WS

Bone microstructure and its associated genetic variability in 12 inbred mouse strains: microCT study and in silico genome scan.

• DOI: 10.1016/j.bone.2007.09.041
• 发表时间: 2008-02
• 期刊: Bone
• 影响因子: 4.1
• 作者: Ilya Sabsovich;J. D. Clark;Guochun Liao;G. Peltz;Derek P. Lindsey;Christopher R. Jacobs;W. Yao;T. Guo;W. Kingery

Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome.

• DOI: 10.1186/1744-8069-8-85
• 发表时间: 2012-11-28
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Guo TZ;Wei T;Shi X;Li WW;Hou S;Wang L;Tsujikawa K;Rice KC;Cheng K;Clark DJ;Kingery WS
• 通讯作者: Kingery WS

Mice lacking substance P have normal bone modeling but diminished bone formation, increased resorption, and accelerated osteopenia with aging.

• DOI: 10.1016/j.bone.2020.115806
• 发表时间: 2021-03
• 期刊: Bone
• 影响因子: 4.1
• 作者: Wang L;Hou S;Sabsovich I;Guo TZ;Wei T;Kingery WS
• 通讯作者: Kingery WS

Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro.

• DOI: 10.1016/j.bone.2009.04.203
• 发表时间: 2009-08
• 期刊: BONE
• 影响因子: 4.1
• 作者: Wang, Liping;Zhao, Rong;Shi, Xiaoyou;Wei, Tzuping;Halloran, Bernard P.;Clark, David J.;Jacobs, Christopher R.;Kingery, Wade S.
• 通讯作者: Kingery, Wade S.