Physical mechanical stimulation can maintain and even increase bone mass. Here, we report an important role of osteocytic integrin α5 in regulating the anabolic response of bone to mechanical loading using an Itga5 conditional gene knockout (cKO) mouse model. Integrin α5 gene deletion increased apoptotic osteocytes and reduced cortical anabolic responses to tibial compression including decreased endosteal osteoblasts and bone formation, and increased endosteal osteoclasts and bone resorption, contributing to the decreased bone area fraction and biomechanical properties, leading to an enlarged bone marrow area in cKO mice. Similar disruption of anabolic responses to mechanical loading was also detected in cKO trabecular bone. Moreover, integrin α5 deficiency impeded load-induced Cx43 hemichannel opening, and production and release of PGE2, an anabolic factor, resulting in attenuated effects of the loading on catabolic sclerostin (SOST) reduction and anabolic β-catenin increase. Together, this study shows an indispensable role of integrin α5 in osteocytes in the anabolic action of mechanical loading on skeletal tissue through activation of hemichannels and PGE2-evoked gene expression. Integrin α5 could act as a potential new therapeutic target for bone loss, especially in the elderly population with impeded mechanical sensitivity.

物理机械刺激可以维持甚至增加骨量。在这里，我们报告了骨细胞整合素 α5 在使用Itga5调节骨骼对机械负荷的合成代谢反应中的重要作用。条件基因敲除（cKO）小鼠模型。整合素α5基因缺失增加了凋亡的骨细胞并减少了对胫骨压迫的皮质合成代谢反应，包括减少骨内成骨细胞和骨形成，增加骨内破骨细胞和骨吸收，导致骨面积分数和生物力学特性降低，导致骨髓面积扩大cKO 小鼠。在 cKO 骨小梁中也检测到对机械负荷的合成代谢反应的类似破坏。此外，整合素 α5 缺乏阻碍了负荷诱导的 Cx43 半通道开放，以及 PGE2（一种合成代谢因子）的产生和释放，导致负荷对分解代谢硬化蛋白 (SOST) 减少和合成代谢 β-连环蛋白增加的影响减弱。一起，这项研究表明整合素 α5 在骨细胞中通过激活半通道和 PGE2 诱发的基因表达，在骨骼组织机械负荷的合成代谢作用中发挥不可或缺的作用。整合素 α5 可以作为骨质流失的潜在新治疗靶点，特别是在机械敏感性受阻的老年人群中。