The Sirt1‐Piezo1 Axis Promotes Bone Formation and Repair in Mice

Abstract The mechanosensitive Piezo1 channel protein plays a pivotal role in promoting bone formation and repair; however, its underlying molecular mechanism(s) are poorly defined. Here this study shows that Sirt1 positively regulates Piezo1 expression and activity to promote osteogenesis and bone repair in mice. This study finds that Piezo1 is up‐regulated in the cartilage callus during bone repair. Deleting Piezo1 in chondrocytes largely impairs endochondral ossification and mechanically induced osteogenesis and delays fracture healing in mice, while Yoda1 activation of Piezo1 exerts opposite effects. Sirt1 overexpression or activation dramatically increases Piezo1 protein expression in a dose‐dependent manner. Sirt1 binds to Piezo1 protein and deacetylates and activates Piezo1 and Ca 2+ influx in chondrocytes. Piezo1 loss in chondrocytes abolishes the ability of Sirt1 activator SRT2104 to accelerate bone repair. Resveratrol (RSV), a natural Sirt1 activator, also potently activates Piezo1 and enhances bone repair. A yeast microcapsule‐based oral formulation of RSV (YC‐RSV) is developed to improve drug bioavailability and therapeutic efficacy, which highly and selectively targets to the inflammatory fracture site. Thus, it demonstrates that Sirt1 is a novel and potent activator of Piezo1 to promote bone formation and repair, supporting the potential clinical application of Sirt1 activators in promoting bone formation and repair.