Mechanical stress overload promotes NF-κB/NLRP3-mediated osteoarthritis synovitis and fibrosis through Piezo1

Mechanical stress is a pivotal factor in the development of knee osteoarthritis (KOA). Piezo1, an innovative mechanosensitive ion channel, plays a key role in detecting variations in mechanical stress and transforming them into electrical signals. This research focuses on examining how Piezo1 influences synovial inflammation and fibrosis induced by mechanical stress in KOA, as well as delving into the potential underlying mechanisms. In vivo, pathological changes and immunohistochemical staining were conducted on both normal and overexercise rat synovial tissues to analyze the expression of Piezo1 and the NF-κB/NLRP3 pathways. In vitro utilized a cell stretcher to replicate the mechanical conditions seen in KOA. Levels of pro-inflammatory cytokines and fibrosis-related markers were assessed to investigate the impact of Piezo1 on mechanical stress in fibroblast-like synoviocytes (FLS). Subsequently, following cell stretching interventions, the effects on synovial inflammation and fibrosis were observed with the use of the Piezo1 inhibitor GsMTx4 or the NLRP3 inhibitor MCC950. Mechanical stress significantly promoted the activation of Piezo1, increased the phosphorylation ratio of p65, and elevated the levels of NLRP3, caspase-1, ASC, GSDMD, IL-1β, IL-18, IL-6, and TNF-α. Both in vitro and in vivo, mechanical stress also promoted the occurrence and development of synovial fibrosis, with significant increases in the expression levels of fibrosis-related markers. Under mechanical stress overload, upregulation of Piezo1 can promote the secretion of pro-inflammatory cytokines and the fibrotic process in synovium through the NF-κB/NLRP3 signaling pathway.