Compressive stress induces cartilage endplate degeneration through the Piezo1/YAP-TEAD/NLRP3 axis

Aims To investigate the potential mechanisms by which compressive stress induces degeneration of cartilage endplate, and to elucidate the specific roles of mechanosensitive protein Piezo1, YAP, and NLRP3 in this process. A pressure-inflammation model of chondrocytes is proposed. Materials and methods Firstly, a bipedal standing mouse model was established to investigate the effect of mechanical stress on cartilage endplate degeneration and calcification. Next, cells were subjected to compression stress and western blot analysis as well as Bulk RNAseq were employed to detect the expression changes of Piezo1, YAP, NLRP3, ASC, and IL-1β. Additionally, intracellular Ca 2+ levels, cytoskeleton and mitochondrial membrane potential were assessed. At last, Piezo1 chondrocyte conditional knockout mice were established to illustrate the role of Piezo1 in mechanical stress induced cartilage endplate degeneration. Key findings The bipedal standing mouse model demonstrated that compressive stress promotes cartilage endplate degeneration. The in vitro experiments demonstrated that compressive stress promoted degeneration of cartilage endplate via Piezo1-induced NLRP3 activation. Compressive stress activate Piezo1, triggering Ca 2+ influx and promoting cytoskeletal polymerization, which facilitated nuclear translocation of YAP. Subsequently, YAP-TEAD complex formation activated the NLRP3 inflammasome, leading to enhanced expression of IL-1β, MMP13, MMP3, RUNX2, and COL10, while suppressing expression of COL2 and SOX9. Significance Our study reveals the role of Piezo1/YAP-TEAD/NLRP3 axis in pressure stress-induced cartilage endplate degeneration. This signaling axis not only regulates inflammation, ossification, and oxidative stress responses in chondrocytes but also promotes chondrocyte apoptosis through mitochondrial dysfunction. These findings provide novel molecular mechanisms for understanding the role of mechanical stress in cartilage degeneration.