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 α5 and αV were activated upon mechanical stimulation via either fluid dropping or flow shear stress (FSS). Inhibition of integrin αV activation or ablation of integrin α5 prevented HC opening on the cell body when dendrites were mechanically stimulated, suggesting mechanical transmission from the dendritic integrin αV to α5 in the cell body during HC activation. In addition, HC function was compromised in vivo, as determined by utilizing an antibody blocking αV activation and α5-deficient osteocyte-specific knockout mice. Furthermore, inhibition of integrin αV activation, but not that of α5, 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 α5 activation and HC opening. Moreover, HC opening was blocked only by an anti-integrin αV antibody at low but not high FSS levels, suggesting that dendritic αV is a more sensitive mechanosensor than α5 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.

机械加载会打开连接蛋白43（Cx43）半通道（HCs），导致机械敏感骨细胞释放骨合成代谢分子（例如前列腺素），这对于骨骼形成和重塑至关重要。然而，激活HC的机械转导机制仍然难以捉摸。在这里，我们报告了一个独特的途径，通过该途径，机械信号可以在位于细胞不同区域的整联蛋白分子之间有效转移，从而导致HC激活。整合素α5和αV均在机械刺激下通过液滴或流切应力（FSS）激活。当树突受到机械刺激时，抑制整联蛋白αV活化或去除整联蛋白α5可防止HC在细胞体上开放，提示在HC激活过程中，从树突整合素αV到细胞体内的α5机械传递。此外，体内的HC功能受到损害，这是通过利用抗体来阻断αV活化和α5缺乏的骨细胞特异性基因敲除小鼠来确定的。此外，抑制整联蛋白αV激活而不抑制α5，在机械负荷下减弱了磷酸肌醇3-激酶（PI3K）-蛋白激酶B（AKT）信号通路的激活，而抑制PI3K / AKT激活则阻断了整联蛋白α5激活。和HC开业。此外，在低但不高FSS水平下，HC开口仅被抗整合素αV抗体阻断，这表明树突状αV是比α5更灵敏的机械传感器，可激活HC。一起，