Osteocytes regulate bone anabolic response to mechanical loading in male mice via activation of integrin alpha 5

Physical mechanical stimulation can maintain and even increase bone mass. Here, we report an important role of osteocytic integrin alpha 5 in regulating the anabolic response of bone to mechanical loading using an Itga5 conditional gene knockout (cKO) mouse model. Integrin alpha 5 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 alpha 5 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 beta-catenin increase. Together, this study shows an indispensable role of integrin alpha 5 in osteocytes in the anabolic action of mechanical loading on skeletal tissue through activation of hemichannels and PGE2-evoked gene expression. Integrin alpha 5 could act as a potential new therapeutic target for bone loss, especially in the elderly population with impeded mechanical sensitivity.