Piezo1 Regulates Fibrocartilage Stem Cell In Cartilage Growth And Osteoarthritis

This study investigates the mechanotransductive role of Piezo1 in fibrocartilage stem cells (FCSCs) during temporomandibular joint (TMJ) development and osteoarthritis pathogenesis, addressing a critical gap in understanding how mechanical cues regulate craniofacial morphogenesis and disease progression. We performed single-cell RNA sequencing (scRNA-seq) on human TMJ samples to assess the expression of mechanosensitive ion channels. Conditional knockout mice were generated to study the effects of Piezo1 on condylar development and homeostasis. Specifically, Gli1-CreERT2; Piezo1 fl/fl mice were used to delete Piezo1 in Gli1+ cells. To model TMJOA, unilateral partial discectomy (UPD) was performed, followed by comprehensive analyses including histology and immunohistochemistry to evaluate the impact of Piezo1 deletion. ScRNA-seq revealed prominent PIEZO1 expression in human condylar cartilage and bone, with Piezo1-tdTomato reporter mice confirming its age-independent expression pattern in murine condyles. Conditional Piezo1 knockout in Gli1+ cells disrupted condylar development and homeostasis by impairing fibrocartilage stem cell differentiation, while Piezo1 deletion in a TMJ osteoarthritis model alleviated pathological symptoms, improved condylar morphology, and reduced cartilage degradation through mechanotransduction modulation. Our findings suggest that Piezo1 serves as a critical mechanosensitive regulator enabling Gli1+ FCSCs to perceive physiological mechanical cues and sustain their differentiation capacity into chondrocytes. Deletion of Piezo1 in a physiological context impairs FCSCs differentiation, while in a pathological state it offers protection against TMJOA-induced damage to the condyle by preventing Gli1+ cells depletion.