CSNK2A2 drives knee osteoarthritis progression by co-activating the Wnt/β-catenin and NF-κB signaling pathways

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. This study aimed to investigate the role of CSNK2A2 in KOA pathogenesis and its regulatory effects on the Wnt/β-catenin and nuclear factor (NF)-κB pathways.

Differentially expressed genes were identified from the GSE117999 dataset. A monosodium iodoacetate (MIA)-induced rat KOA model was established. Synovial tissues were collected for histological, micro-CT, and molecular analyses. Rat synovial cells (RSCs) were stimulated with interleukin (IL)-1β to mimic an in vitro KOA model. CSNK2A2 was knocked down using shRNA, and the β-catenin pathway was activated with C91. Synovial tissues from KOA patients and healthy controls were also collected to validate CSNK2A2 expression. Gene and protein expression levels were assessed by reverse transcription-quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, immunofluorescence, and immunohistochemistry. Joint damage was scored using the OARSI system.

CSNK2A2 was upregulated in both in vivo and in vitro KOA models and in the synovial tissues of KOA patients. Knockdown of CSNK2A2 attenuated cartilage destruction, reduced pro-inflammatory cytokine production, preserved proteoglycan content, and improved subchondral bone microstructure. In RSCs, CSNK2A2 silencing suppressed inflammation, extracellular matrix degradation, and apoptosis induced by IL-1β. Mechanistically, CSNK2A2 knockdown increased GSK3β and decreased β-catenin and p-p65 expression, indicating inhibition of both Wnt/β-catenin and NF-κB signaling, and immunofluorescence confirmed that CSNK2A2 knockdown reduced p65 nuclear translocation, which was restored by C91. Conversely, activation of β-catenin with C91 reversed the protective effects of CSNK2A2 knockdown in both cellular and animal models.

CSNK2A2 promoted KOA progression by activating the Wnt/β-catenin and NF-κB pathways, thereby driving inflammation, matrix degradation, and chondrocyte apoptosis.