Piezo1 Activation Rescues Anabolic Response to Mechanical Loading in Aged Bone via Connexin 43 Hemichannels

ABSTRACT Bone mechanosensitivity declines with age, resulting in a reduced anabolic response to mechanical stimulation. Although the mechanosensitive ion channel Piezo1 plays a critical role in bone mechanoresponsiveness, its mechanisms of mechanotransduction in aged bone remain incompletely understood. Here, we report that aged tibiae from 19‐month‐old male mice exhibit a blunted anabolic response to axial cyclic compressive loading or administration of the Piezo1 agonist Yoda1 alone. However, chemical activation of osteocytic Piezo1 by Yoda1 effectively rescues the anabolic response of aged cortical bone to mechanical loading. Mechanistically, Yoda1‐induced Piezo1 activation promotes its co‐localization with connexin 43 (Cx43) on the osteocyte membrane in response to mechanical stimulation. This Piezo1‐Cx43 interaction enhances Cx43 hemichannel (HC) activity via the PI3K‐Akt signaling pathway. Subsequent HC opening facilitates the release of the anabolic factor prostaglandin E 2 (PGE 2 ) and suppresses the catabolic factor sclerostin (SOST), thereby promoting bone formation and inhibiting bone resorption on the endosteal surface, which ultimately increases cortical bone mass during mechanical loading. Collectively, our findings reveal a mechanism whereby Piezo1 mediates the skeletal anabolic response to mechanical loading in aged bone via Cx43 HCs, offering new perspectives for combating age‐related osteoporosis.