NEURAL REGULATION OF BONE REMODELING

骨重塑的神经调节

基本信息

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
项目类别：
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

项目摘要

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病，其特征是骨量低和微结构完整性丧失，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仅部分有效。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可以影响骨代谢，并且该信号的丢失可能会导致骨质疏松症的发生。该提案将使用免疫组织化学和实时 PCR 来识别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测定。体内方法是全身施用感觉神经递质受体拮抗剂，并通过直接局部输注到大鼠的近端胫骨中来确定这些递质的内源性释放是否是维持骨完整性所必需的。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，包括远程骨质疏松模型，其中在单侧感觉损伤或后肢固定后对侧后肢失去骨质、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将被直接注入骨质疏松大鼠的胫骨中，以试图扭转骨质流失并增加骨强度。另一项研究将确定长期鞘内注射 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) 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骼中，3) 验证它们对于体内骨骼完整性的保存是必需的，4 ) 确定背根神经节切除术和固定后这些递质在骨中耗尽，并且 5) 证明这些递质的恢复可以逆转神经创伤和远端骨质疏松的影响固定化。这些研究将有助于识别调节骨重塑的感觉递质并表征它们在骨质疏松过程中的作用。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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.