Mechanotransduction via the coordinated actions of integrins,PI3K signaling and Connexin hemichannels  

作　　者：Manuel A.Riquelme Sumin Gu Rui Hua Jean X.Jiang 

机构地区：[1]Department of Biochemistry and Structural Biology,University of Texas Health Science Center,San Antonio,TX 78229-3900,USA

出　　处：《Bone Research》2021年第1期86-96,共11页骨研究（英文版）

基　　金：the National Institutes of Health(NIH)grant AR072072(to J.X.J.);the Welch Foundation grant AQ-1507(to J.X.J.).We also thank the UTHSCSA CMMI and the UTHSCSA Optical Imaging Facility supported by the Cancer Therapy and Research Center for the support provided from the NIH-National Cancer Institute P30 award CA054174 and Texas state funds.

摘　　要：Mechanical loading opens connexin 43(Cx43)hemichannels(HCs),leading to the release of bone anabolic molecules,such as prostaglandins,from mechanosensitive osteocytes,which is essential for bone formation and remodeling.However,the mechanotransduction mechanism that activates HCs remains elusive.Here,we report a unique pathway by which mechanical signals are effectively transferred between integrin molecules located in different regions of the cell,resulting in HC activation.Both integrinα5 andαV were activated upon mechanical stimulation via either fluid dropping or flow shear stress(FSS).Inhibition of integrinαV activation or ablation of integrinα5 prevented HC opening on the cell body when dendrites were mechanically stimulated,suggesting mechanical transmission from the dendritic integrinαV toα5 in the cell body during HC activation.In addition,HC function was compromised in vivo,as determined by utilizing an antibody blockingαV activation andα5-deficient osteocyte-specific knockout mice.Furthermore,inhibition of integrinαV activation,but not that ofα5,attenuated activation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT)signaling pathway upon mechanical loading,and the inhibition of PI3K/AKT activation blocked integrinα5 activation and HC opening.Moreover,HC opening was blocked only by an anti-integrinαV antibody at low but not high FSS levels,suggesting that dendriticαV is a more sensitive mechanosensor thanα5 for activating HCs.Together,these results reveal a new molecular mechanism of mechanotransduction involving the coordinated actions of integrins and PI3K/AKT in osteocytic dendritic processes and cell bodies that leads to HC opening and the release of key bone anabolic factors.

关 键 词：PI3K/AKT stimulation COORDINATED 

分 类 号：R336[医药卫生—人体生理学]