IκB kinase epsilon deficiency attenuates osteoarthritis-associated pain and synovitis with limited cartilage protection in complementary mouse models

Osteoarthritis is a whole-joint disease characterized by cartilage degeneration, synovial inflammation, and chronic pain, yet the causal role of IκB kinase epsilon (IKKε) in these distinct disease components remains unclear. We therefore investigated whether IKKε contributes to structural joint degeneration, synovial inflammation, and OA-associated pain using complementary in vitro and in vivo analyses in IKKε-deficient mice. IKKε deficiency reduced c-Jun phosphorylation, decreased Mmp13 expression in primary chondrocytes, and decreased Ccl2 expression in synovial cells, whereas p65 phosphorylation did not differ significantly between genotypes. In vivo, IKKε deficiency attenuated synovitis and mechanical hypersensitivity in the MIA model. In the DMM + MCLT model, inflammatory and catabolic markers in cartilage were reduced, whereas no statistically significant reduction in histological cartilage degeneration was detected. IKKε-deficient chondrocytes also showed increased Ikkβ and Tbk1 expression, which may represent a potential adaptive response, although functional compensation was not established. Together, these findings show that IKKε deficiency attenuates OA-associated synovitis and pain-related behavior and alters cartilage inflammatory and catabolic signaling, while its effect on structural cartilage degeneration remains uncertain, supporting the potential of IKKε as a therapeutic target for OA pain and synovial pathology.