Cyclic distraction-compression promotes bone regeneration during distraction osteogenesis through the Piezo1-YAP-β-catenin axis.

Background: Distraction osteogenesis (DO) is an effective reconstructive strategy for large bone defects, but its clinical application is constrained by slow regenerate maturation and prolonged consolidation. The cyclic distraction-compression (CDC, accordion technique) has shown promise in enhancing bone formation; however, its underlying mechanotransduction mechanisms remain poorly understood. Methods: A rat femoral DO model was established and CDC was applied during the mid-consolidation phase. To interrogate mechanistic pathways, a Piezo1 agonist (Yoda1) or inhibitor (GsMTx4) was locally administered. Bone regeneration was evaluated by serial radiography, micro-computed tomography, biomechanical testing, histomorphology, and immunohistochemical analyses. Results: CDC significantly enhanced regenerate bone volume, mineral density, structural continuity, and mechanical properties compared with controls. Activation of Piezo1 further amplified these effects, whereas Piezo1 inhibition attenuated CDC-induced improvements. At the molecular level, CDC increased the expression of Piezo1, YAP, and β-catenin, accompanied by elevated osteogenic markers (RUNX2, OPN) and angiogenic markers (VEGF, CD31). These findings indicate that CDC promotes coupled osteogenesis and angiogenesis within the distraction regenerate through Piezo1-dependent signaling. Conclusion: Our study suggests that CDC accelerates bone regeneration during distraction osteogenesis, potentially through Piezo1-YAP-β-catenin-associated signaling and enhanced osteogenic-angiogenic coupling. These results provide mechanistic insight into the accordion technique and support the development of optimized mechanical and mechanosensory-targeted strategies to improve DO outcomes.