GsMTx4 Alleviates Knee Osteoarthritis by Inhibiting PIEZO1/2-mediated Chondrocyte Apoptosis

Knee osteoarthritis (KOA) is a prevalent, disabling degenerative joint disorder featuring progressive articular cartilage loss, persistent chronic pain, and compromised knee mobility. This work aimed to characterize the expression pattern of mechanosensitive ion channels PIEZO1/2 in KOA and explore their potential regulatory roles, as well as preliminarily evaluate whether non-selective PIEZO inhibitor GsMTx4 could slow KOA-related pathological changes.

Cartilage tissues and matched clinical data were collected from 54 KOA patients undergoing knee arthroplasty, and 20 trauma patients with intact cartilage served as controls. Correlations between PIEZO1/2 abundance, clinical pain severity, and radiographic grades were analyzed. A rat posttraumatic KOA model was established via anterior cruciate ligament, medial collateral ligament, and partial medial meniscus resection, followed by weekly intra-articular GsMTx4 injection for 8 weeks. Pain behaviors and cartilage histology were assessed. Transcriptomic profiling and bioinformatic analysis were carried out, and core differentially expressed genes were further verified via immunohistochemistry.

PIEZO1/2 expression was markedly increased in KOA cartilage, and their upregulation showed positive correlations with aggravated pain and higher Kellgren-Lawrence grades. In animal assays, GsMTx4 treatment appeared to alleviate hyperalgesia, attenuate chondrocyte apoptosis and cartilage damage, and partially rescue KOA-associated fibrotic remodeling, lipid metabolic imbalance, and inflammatory dysregulation.

Aberrant PIEZO1/2 upregulation and activation may be linked to chondrocyte apoptosis, cartilage degeneration, and pain hypersensitivity in KOA. Blocking PIEZO channels with GsMTx4 might mitigate pathological joint remodeling, suggesting PIEZO channels could represent potential therapeutic targets for KOA intervention.