Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood...Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood.This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification.Using lineage tracing,we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification,which was impaired by chondrocyte-specific Piezo1 knockout.Piezo1 deficiency disrupted mitochondrial bioenergetics,characterized by diminished membrane potential,reduced adenosine triphosphate(ATP)synthesis,suppressed oxygen consumption rates(basal and maximal respiration),and elevated mitochondrial superoxide generation,thereby impairing endochondral ossification during fracture healing.Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout.Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers(MFN1,MFN2,OPA1,DRP1)and restored mitochondrial functional homeostasis.This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers(Col1,ALP,OCN,OPN,RUNX2),thereby enhancing fracture repair.Protein interaction analyses confirmed direct binding betweenβ-catenin and Lars2.Mechanistically,Piezo1 governs Lars2 expression viaβ-catenin signaling.Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through theβ-catenin/Lars2 axis,offering novel insights and therapeutic avenues for fracture treatment.展开更多
基金supported by the Key Projects of the National Natural Science Foundation of China(Grant No.32130052)the National Natural Science Youth Foundation of China(Grant No.82102584)Natural Science Foundation of Hebei Province(CN)-for Yanzhao Young Scientists Project(Grant No.H2023206519).
文摘Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood.This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification.Using lineage tracing,we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification,which was impaired by chondrocyte-specific Piezo1 knockout.Piezo1 deficiency disrupted mitochondrial bioenergetics,characterized by diminished membrane potential,reduced adenosine triphosphate(ATP)synthesis,suppressed oxygen consumption rates(basal and maximal respiration),and elevated mitochondrial superoxide generation,thereby impairing endochondral ossification during fracture healing.Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout.Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers(MFN1,MFN2,OPA1,DRP1)and restored mitochondrial functional homeostasis.This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers(Col1,ALP,OCN,OPN,RUNX2),thereby enhancing fracture repair.Protein interaction analyses confirmed direct binding betweenβ-catenin and Lars2.Mechanistically,Piezo1 governs Lars2 expression viaβ-catenin signaling.Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through theβ-catenin/Lars2 axis,offering novel insights and therapeutic avenues for fracture treatment.
