PIEZO1 mediates orthodontic tension force-induced alveolar bone remodeling via the Ca²⁺/YAP-TAZ pathway in periodontal ligament stem cells

BACKGROUND: Periodontal ligament stem cells (PDLSCs) orchestrate alveolar bone remodeling during orthodontic tooth movement (OTM), yet the molecular mechanism translating tension force into coupled osteogenic and anti-osteoclastic responses remains elusive. This study aimed to define the dual mechanosensitive role of PIEZO1 in PDLSCs for simultaneously promoting osteogenesis and suppressing osteoclastogenesis via the Ca²⁺/YAP-TAZ/OPG-RANKL signaling axis. METHODS: Human PDLSCs were isolated, characterized for mesenchymal markers, and exposed to cyclic tension (10% strain, 0.5 Hz) using a Flexcell system. PIEZO1 was inhibited using GsMTx4 or siRNA, and Ca²⁺ flux was analyzed by live-cell confocal microscopy. Osteogenic (RUNX2, OSX), osteoclastic (RANKL, OPG), and YAP/TAZ signaling markers were assessed using RT-qPCR and Western blot. For in vivo validation, a rat OTM model was established using 40-g NiTi springs. Tooth movement and tension-side alveolar bone remodeling were quantified by micro-CT, while osteogenic and osteoclastic activities were evaluated through immunohistochemistry and TRAP staining. RESULTS: Tension force activated PIEZO1 channels, triggering rapid Ca²⁺ influx and subsequent nuclear accumulation of YAP/TAZ. YAP/TAZ activation transcriptionally upregulated RUNX2 and OSX, concurrently reprogramming the PDLSC secretome to favor Osteoprotegerin (OPG) dominance over RANKL, significantly reducing the RANKL/OPG ratio and thus suppressing osteoclast differentiation. Pharmacological inhibition of PIEZO1 (GsMTx4) or genetic knockdown abrogated Ca²⁺ influx, prevented YAP/TAZ nuclear translocation, and disrupted the RANKL/OPG balance, thereby uncoupling osteogenesis from osteoclast suppression both in vitro and in vivo. CONCLUSIONS: This study defines a fundamental mechanotransduction cascade initiated by PIEZO1, wherein Ca²⁺ influx mobilizes YAP/TAZ nuclear translocation to transcriptionally activate osteogenic differentiation and reprogram anti-osteoclastic secretory profiles. Deciphering this mechanocode nominates PIEZO1 as a promising therapeutic target for recalibrating bone remodeling balance and mitigating pathological bone loss during orthodontic therapy.