Promotion of Knee Cartilage Degradation by I kappa B Kinase epsilon in the Pathogenesis of Osteoarthritis in Human and Murine Models

Objective. NF-kappa B signaling is an important modulator in osteoarthritis (OA), and I kappa B kinase epsilon (IKK epsilon) regulates the NF-kappa B pathway. This study was undertaken to identify the functional involvement of IKK epsilon in the pathogenesis of OA and the effectiveness of IKK epsilon inhibition as a modulatory treatment.Methods. IKK epsilon expression in normal and OA human knee joints was analyzed immunohistochemically. Gain-or loss-of-function experiments were performed using human chondrocytes. Furthermore, OA was surgically induced in mice, followed by intraarticular injection of BAY-985, an IKK epsilon/TANK-binding kinase 1 inhibitor, into the left knee joint every 5 days for 8 weeks. Mice were subsequently examined for histologic features of cartilage damage and inflammation.Results. IKK epsilon protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related fac-tors were down-regulated following knockdown of IKK epsilon with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY-985. Conversely, IKK epsilon overexpression significantly increased the expression of OA-related catabolic mediators. In Western blot analysis of human chondrocytes, IKK epsilon overexpression increased the phosphorylation of I kappa Ba and p65. In vivo, intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia via NF-kappa B signaling.Conclusion. These results suggest that IKK epsilon regulates cartilage degradation through a catabolic response mediated by NF-kappa B signaling, and this could represent a potential target for OA treatment. Furthermore, BAY-985 may serve as a major disease-modifying compound among the drugs developed for OA.