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Osteocyte Mechanotransduction and the Gabapentin-Sensitive Matrix-Channel Tethering Complex

骨细胞机械转导和加巴喷丁敏感基质通道束缚复合物

基本信息

批准号：
10428360
负责人：
William Roy Thompson
金额：
$ 59.41万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428360
关键词：
Ablation Acute Address Affinity Alleles Antiepileptic Agents Behavior Binding Biochemical Biochemistry Biological Bone Matrix Bone Resorption Calcium Channel Cell membrane Cell surface Cells Chronic Clinical Combined Modality Therapy Complex Confocal Microscopy Cues Disease Elements Fracture Genetic Heparan Sulfate Proteoglycan Histologic Hormonal Image Impairment In Vitro Knockout Mice Ligands Liquid substance LoxP-flanked allele Maintenance Measures Mechanics Membrane Methods Molecular Morbidity - disease rate Mus Musculoskeletal Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteopenia Patients Pharmaceutical Preparations Positioning Attribute Protocols documentation Regimen Rehabilitation therapy Signal Transduction Skeleton Structure Surface Plasmon Resonance System Techniques Time Tissues Work bone bone cell bone loss bone mass bone quality bone strength density dentin matrix protein 1 design disability extracellular fracture risk gabapentin genetic approach in vivo insight knock-down mechanical force mechanical load mechanical signal mechanical stimulus mechanotransduction mineralization mouse model novel novel strategies painful neuropathy perlecan pharmacologic preservation prevent receptor response sedentary lifestyle side effect skeletal transmission process voltage

项目摘要

Project Summary The skeleton relies on a variety of mechanical, biochemical, and hormonal cues to regulate bone strength, structure, and mass. Osteocytes are both the most abundant and most mechanosensitive cells within bone. Located deep in the bone matrix, these cells are optimally positioned to sense and respond to force, directing the activity of other skeletal cells, including osteoblasts and osteoclasts. A variety of molecules influence osteocyte mechanosensation; however, how force is directly transmitted from the mineralized matrix to the cell membrane to induce a biological response remains unknown. We have identified the presence of a complex within osteocytes composed of extracellular perlecan/HSPG2 and a cell surface subunit (a2d1) of voltage sensitive calcium channels (VSCCs). As the perlecan-containing tethers bind the a2d1 subunit of VSCCs, this Matrix-Channel Tethering Complex (M-CTC) enables direct connection between the mineralized matrix and the cell membrane. Thus, the proposed studies will dissect how this mechanosensory complex mechanistically regulates osteocyte behavior, under both basal and mechanical loading conditions. Additionally, the a2d1 subunit of the complex is the receptor for the commonly used antiepileptic and neuropathic pain drug, gabapentin, which can have severe adverse skeletal side effects. Thus, this work will not only investigate the foundational mechanisms through which osteocytes sense force, but will also inform the design of novel strategies to offset the negative effects of gabapentin on bone that reduce bone mass. Our overarching hypothesis is that perlecan-containing tethers, within the M-CTC, transmit force to the a2d1 subunit of VSCCs, enabling mechanical signals to be transduced into anabolic biochemical responses in osteocytes. Aim 1: Determine if osteocyte-specific disruption of the M-CTC membrane receptor a2d1 impairs basal or load-induced bone formation with resultant loss in bone quality. Aim 2: Determine if tissue-specific genetic ablation of the PLN matrix tethers within the M-CTC of osteocytes impairs basal or load-induced bone formation with resultant loss in bone quality. Aim 3: Determine how gabapentin interferes with the M-CTC to impair basal and load-induced bone formation. The function of the M-CTC has not been explored in vivo. As such, these integrated studies, designed to genetically and pharmacologically disrupt the M-CTC and assess the functional consequences, will provide basic insights into the relationship between extracellular tethers and calcium channels in bone. In the long term, this understanding may reduce bone loss in patients treated with gabapentin for neuropathic pain.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of Dietary Protein Source and Quantity on Bone Morphology and Body Composition Following a High-Protein Weight-Loss Diet in a Rat Model for Postmenopausal Obesity.

DOI：
10.3390/nu14112262
发表时间：
2022-05-28
期刊：
NUTRIENTS
影响因子：
5.9
作者：
Wright, Christian S.;Hill, Erica R.;Reyes Fernandez, Perla C.;Thompson, William R.;Gallant, Maxime A.;Campbell, Wayne W.;Main, Russell P.
通讯作者：
Main, Russell P.

The bone-muscle connection in breast cancer: implications and therapeutic strategies to preserve musculoskeletal health.