Therapeutic potential of IκB kinase epsilon inhibition in preventing meniscal degeneration of early osteoarthritis.

Aims: Meniscal degeneration may precede or indicate early-stage osteoarthritis (OA); however, the pathogenetic involvement of the NF-κB pathway and its upstream IκB kinase (IKK) is unclear. This study investigated the functional role of IKK in the pathogenesis of meniscal degeneration, and the efficacy of IKKε inhibition as a therapeutic approach. Methods: IKK expression in normal and OA human menisci was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed in human meniscal cells. Additionally, meniscal degeneration was induced in wild-type mice and treated with intra-articular injection of the IKKε/TBK1 inhibitors amlexanox and BAY-985 every five days for four weeks. Meniscal degeneration was also induced in IKKε knockout mice. Mice were subsequently examined histologically. Results: IKK protein expression was increased in human OA menisci. In vitro, the expression of meniscal degeneration-related factors was decreased after knockdown of each Conclusion: These results indicate that IKKs are involved in meniscal degeneration when it constitutes the preliminary or early stage of OA, with IKKε possibly playing a significant role. Furthermore, IKKε regulates meniscal degeneration through NF-κB signalling-mediated catabolism. Two IKKε/TBK1 inhibitors, amlexanox and BAY-985, are potential targets for the treatment of meniscal degeneration prior to OA.