PSMB9 Exacerbates Chondrocyte Injury in Osteoarthritis via Activation of the NF-κB Pathway

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and synovial inflammation, with its pathogenesis being incompletely understood. This study aimed to investigate the role and mechanism of PSMB9 in interleukin-1β (IL-1β)-induced chondrocyte injury. Methods: We identified OA-associated proteasome members by analyzing public datasets (including GSE215039). PSMB9 expression was assessed in clinical OA samples and OA model mouse tissues via immunohistochemistry. The functional roles of PSMB9 and its regulation of the NF-κB pathway in IL-1β-induced human C28/I2 chondrocytes were examined using Western blot, CCK-8, EdU, and flow cytometry assays. The effect of IL-6 knockdown on PSMB9 expression was also evaluated by Western blot. Results: (1) PSMB9 was a common differentially expressed gene in multiple human and mouse OA datasets. (2) Its expression was significantly upregulated in human OA cartilage, mouse OA models, and IL-1β-stimulated primary and C28/I2 chondrocytes. (3) Overexpression of PSMB9 promoted apoptosis, inhibited proliferation, increased levels of the pro-inflammatory cytokine IL-6 and the matrix-degrading enzyme MMP13, enhanced extracellular matrix (ECM) degradation, and reduced collagen type II alpha 1 (COL2A1) expression. (4) PSMB9 activated the NF-κB pathway by promoting IκBα degradation, and inhibition of NF-κB signaling alleviated the chondrocyte injury. (5) Silencing IL-6 reduced PSMB9 expression. Conclusion: PSMB9 exacerbates OA chondrocyte injury by activating the NF-κB pathway, suggesting its potential as a therapeutic target for OA.