Macrophage piezo1 senses mechanical force to drive osteoclastogenesis via ZBP1: Implications for bone remodelling therapy

Abstract Background The unpredictability of orthodontic tooth movement (OTM) and risks of root resorption stem from poorly understood mechanisms governing alveolar bone remodelling. Specifically, how macrophages transduce mechanical forces into osteoclastogenic signals remains elusive. Methods Our integrated approach combined analyses at multiple levels: clinical analysis of human periodontal ligament (PDL) tissues via qPCR and immunofluorescence; in vivo functional assessment using murine OTM and fracture models with macrophage‐specific knockouts (for Piezo1 and Z‐DNA binding protein 1 ( Zbp1 ), designated as Piezo1 cko and Zbp1 cko ); and in vitro mechanistic investigation through RNA sequencing of murine bone marrow‐derived macrophages (BMDMs) and pharmacological screening. This multi‐faceted strategy was employed to dissect the pathway. Results Mechanical stress activated macrophage Piezo1, triggering Ca 2+ influx and subsequent upregulation of ZBP1. This axis was essential for pro‐inflammatory cytokine release and osteoclastogenesis. Macrophage‐specific deletion of Piezo1 or Zbp1 significantly decelerated OTM and preserved alveolar bone mass. Notably, Zbp1 overexpression rescued the remodelling defects in Piezo1 ‐deficient mice. Virtual screening identified JNJ‐10311795 as a ZBP1 modulator; its administration effectively slowed OTM and, conversely, accelerated fracture healing by shifting the balance towards bone formation. Conclusion The Piezo1–ZBP1 axis constitutes a novel mechano‐immune switch converting physical stress into inflammation and bone resorption. Pharmacological targeting of this axis offers a bidirectional therapeutic strategy for controlling orthodontic movement and enhancing bone repair.