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Connexin channels in transducing mechanical signals in bone

连接蛋白通道在骨中转导机械信号

基本信息

批准号：
9754577
负责人：
Jean X Jiang
金额：
$ 33.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754577
关键词：
Animal Model Antibodies Attenuated Biological Biomechanics Blocking Antibodies Bone Diseases Bone Matrix Bone Resorption Bone Tissue Bone remodeling Cell Survival Cells Cellular Mechanotransduction Complement Connexin 43 Connexins Cytoskeleton Data Development Dinoprostone Dominant-Negative Mutation Environment Gap Junctions Genes Impairment In Situ In Vitro Integrins Knock-in Mouse Knockout Mice Location MAP Kinase Gene Mechanical Stimulation Mechanical Stress Mechanics Mediating Minerals Modality Modeling Molecular Mutation Osteocytes Osteogenesis Osteopenia Osteoporosis Outcome Phenotype Physiological Play Property Prostaglandins Regulation Research Research Activity Role Signal Transduction TNFSF11 gene Testing Therapeutic Therapeutic Agents Transgenic Mice Transgenic Model WNT Signaling Pathway bone bone cell bone loss cell type drug candidate experience extracellular gap junction channel in vivo knockout gene mechanical load mechanotransduction mouse model mutant new therapeutic target novel novel strategies novel therapeutics response skeletal tissue treatment strategy

项目摘要

Project Summary Mechanical loading experienced by skeletal tissues plays an important role in bone formation and remodeling. Osteocytes are the most abundant bone cell type and the major mechanosensory cells of the bone. They orchestrate bone remodeling from their location throughout bone matrix by coordinating osteoblastic formation and osteoclastic resorption. Osteocytes are connected to neighboring osteocytes and other bone cells via gap junction channels and to extracellular environments via hemichannels. Both types of channels are formed by connexin (Cx) 43. The involvement of Cx43 in response to mechanical stimulation of bone tissue has been shown in gene knockout models; however, the distinct functions of gap junction channels and hemichannels in osteocytes, as well as the mechanism underlying the physiological roles of these channels during mechanical loading remain largely unknown. To dissect the physiological roles of these two types of channels, we have recently developed two transgenic mouse models expressing Cx43 dominant negative mutants predominantly in osteocytes. We are also generating a Cx43 mutant gene knockin mouse model to complement our transgenic models. These mutations impair osteocytic gap junction channels and/or hemichannels. In addition, we have generated antibodies that specifically inhibit Cx43 hemichannels, but not gap junction channels. Moreover, we have developed novel approaches that allow us to assess osteocytic hemichannel activity in situ. Preliminary data show that impairment of Cx43 hemichannels attenuates the anabolic effect of mechanical loading on the bone. We and others have also shown that osteocytic Cx43 hemichannels are opened by mechanical stress, releasing small bone anabolic factors including prostaglandins in vitro. The objective is to determine the specific mechanistic role of Cx43 hemichannels in mediating the anabolic effect of mechanical loading on the skeletal tissues. Three specific aims are proposed: 1) To test the hypothesis that osteocytic Cx43 hemichannels play a crucial role in mediating anabolic function of mechanical loading on skeletal tissue. 2) To test the hypothesis that osteocytic Cx43 hemichannels mediate anabolic function of mechanical loading via PGE2 release, and activation of PGE2 and Wnt signaling. 3) To test the hypothesis that activation and inactivation of Cx43 hemichannels are specifically regulated by integrin activation/cytoskeleton and MAPK signaling, respectively. The proposed studies are expected to have a major positive impact by defining the mechanical transduction mechanism and its regulation in bone tissue, constituting potential, significant contributions toward the development of new therapeutic agents for the treatment of osteoporosis and bone loss.

项目总结