Targeting IKK epsilon to Prevent Meniscal Degeneration in Osteoarthritis: Insights from Human Tissue and Mouse Models

Abstract Objective. 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 intraarticular injection of the IKKε inhibitors amlexanox and BAY-985 every 5 days for 4 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 IKK, particularly IKKε, using small interfering RNA in human OA meniscal cells. Conversely, IKKε overexpression significantly increased the expression of these factors, and amlexanox and BAY-985 canceled this effect. Western blot analysis showed that IKKε overexpression increased IκBα and p65 phosphorylation. In vivo, both IKKε deletion and intraarticular injection of IKKε inhibitors protected mouse menisci against degeneration. 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 signaling–mediated catabolism. Two IKKε inhibitors, amlexanox and BAY-985, are potential targets for the treatment of meniscal degeneration prior to OA.