Piezo1-mediated mechanotransduction controls osteocyte maturation and dendrite development via a YAP-CCN-Src signaling axis.

Mechanical force controls bone development and homeostasis, with mechanosensitive osteocytes playing a key role. Osteocytes form interconnected dendrites to respond to mechanical stimuli and regulate bone formation and resorption. However, the molecular mechanisms underlying osteocyte maturation and dendrite formation remain elusive. Here we show that Piezo1 loss in late osteoblasts and osteocytes reduces bone mass and disrupts osteocyte differentiation with reduced dendrite number, length and network formation. Decreased YAP activity and unexpected Wnt/β-catenin signaling activation cause these deficiencies, largely restored by intermittent YAP activation. We further identify YAP targets CCN1/2 as crucial secreted factors in the Piezo1-YAP mechanotransduction. CCN1/2 overexpression in the liver rescues dendritic and bone defects in the Piezo1 mutant mice by activating Src, promoting actin polymerization, and activating YAP in a positive feedforward loop. Our findings highlight the pivotal roles of Piezo1 and YAP-CCN1/2-Src signaling, offering potential therapeutic targets for improving osteocyte dendritic networks.