Piezo1 mediates hypoxia and mineralization in cementoblasts.

Orthodontically induced inflammatory root resorption (OIIRR) is a common complication associated with excessive compressive force during orthodontic treatment, leading to irreversible cementum destruction. However, the cellular and molecular mechanisms underlying this process remain unclear. This study aimed to investigate the role of the mechanosensitive ion channel Piezo1 in regulating cementoblast function under mechanical stress. Cementoblasts (OCCM-30) were subjected to 1 g/cm2 of compressive force, and global gene expression was analyzed via RNA sequencing, revealing 6932 differentially expressed genes. Compressive force upregulated the expression of HIF-1α and its downstream angiogenesis-related genes (Vegf, Angpt1, Angptl4), while significantly downregulating osteogenic markers such as RUNX2 and SP7, leading to suppressed mineralization and calcium nodule formation. Activation of Piezo1 using the agonist Yoda1 mimicked the effects of compressive force, whereas inhibition by GSMTX4 reversed them. Interestingly, depletion of extracellular calcium did not affect these outcomes, suggesting that Piezo1 acts independently of calcium influx in this context. Moreover, Piezo1 activation and compressive force co-upregulated LIM and cysteine-rich domains 1 (LMCD1) and downregulated Periostin (POSTN), both of which were identified as novel downstream effectors of Piezo1 signaling. These changes were also reversed by Piezo1 inhibition. In conclusion, compressive force impairs cementoblast mineralization while enhancing hypoxia and angiogenic pathways through Piezo1 activation. LMCD1 and POSTN may serve as new molecular targets for understanding and potentially preventing OIIRR. This study provides important insights into the mechanotransduction mechanisms in cementoblasts and identifies Piezo1 as a key regulator linking mechanical stimuli to pathological root resorption.