Pharmacological CK2 inhibition attenuates osteoarthritis associated with CK2β-driven inflammatory signaling

Background The progression of osteoarthritis (OA), a degenerative joint disease, is closely associated with dysregulated inflammatory and catabolic signaling, in which nuclear factor-kappa B (NF-κB) plays a central role. Although casein kinase 2 (CK2) is a major NF-κB regulator, the specific role of subunit CK2β in OA pathogenesis remains unclear. Here, we aimed to investigate the role of CK2β regulation in OA progression. Methods CK2β expression and CK2 kinase activity were examined in cartilage obtained from patients with OA by immunohistochemistry and kinase activity assays. In vitro CSNK2B knockdown was performed in tumor necrosis factor alpha-stimulated human chondrocytes to evaluate inflammatory and catabolic gene expression. The role of CK2β in vivo was further investigated using cartilage-specific Csnk2b conditional knockout mice after destabilization of the medial meniscus (DMM) surgery. In addition, the effect of CK2 inhibition with CX-4945 was evaluated in both DMM- and monosodium iodoacetate (MIA)-induced OA models. Results CK2β expression and CK2 kinase activity were increased in damaged regions of human OA cartilage compared with relatively intact regions. Phosphorylation of p65 and IκB was also higher in damaged cartilage, indicating enhanced NF-κB signaling. Under inflammatory conditions, CK2β was associated with components of the NF-κB pathway. Knockdown of CSNK2B reduced IκBα ubiquitination and NF-κB transcriptional activity and decreased the expression of inflammatory and cartilage-degrading factors. At the same time, cartilage-related marker expression was partially preserved. In mice, cartilage-specific deletion of Csnk2b reduced cartilage degeneration after DMM surgery and was accompanied by lower NF-κB-associated signaling. Pharmacological CK2 inhibition with CX-4945 reduced cartilage damage in both DMM and MIA models and partially improved OA-associated functional changes. Conclusions These findings identify CK2β as a disease-associated regulator of inflammatory and catabolic signaling in OA and support pharmacological CK2 inhibition as a potential strategy to attenuate cartilage degeneration.