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

ABSTRACT: 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 integrin ?5 and ?V were activated upon mechanical stimulation via either fluid dropping or flow shear stress (FSS). Inhibition of integrin ?V activation or ablation of integrin ?5 prevented HC opening on the cell body when dendrites were mechanically stimulated, suggesting mechanical transmission from the dendritic integrin ?V to ?5 in the cell body during HC activation. In addition, HC function was compromised in vivo, as determined by utilizing an antibody blocking ?V activation and ?5-deficient osteocyte-specific knockout mice. Furthermore, inhibition of integrin ?V activation, but not that of ?5, 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 integrin ?5 activation and HC opening. Moreover, HC opening was blocked only by an anti-integrin ?V antibody at low but not high FSS levels, suggesting that dendritic ?V is a more sensitive mechanosensor than ?5 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.

SUBMITTER: Riquelme MA 

PROVIDER: S-EPMC7854719 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature