Promotion of Knee Cartilage Degradation by IκB Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models

Abstract

Objective. NF-κB signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε in the pathogenesis of OA and the effectiveness of IKKε inhibition as a modulatory treatment.Methods. IKKε 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 IKKε/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. IKKε protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors were down-regulated following knockdown of IKKε with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY-985. Conversely, IKKε overexpression significantly increased the expression of OA-related catabolic mediators. In Western blot analysis of human chondrocytes, IKKε overexpression increased the phosphorylation of IκBα and p65. In vivo, intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia via NF-κB signaling.Conclusion. These results suggest that IKKε regulates cartilage degradation through a catabolic response mediated by NF-κB 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.

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

“…Mice were assigned to the two groups using a random number table. Each group contained 7 mice, and group sizes were decided on the basis of a power analysis; at least 7 mice per group were required to detect a minimum difference of 30% between mice postoperatively receiving amlexanox or BAY-985 versus saline in terms of meniscal degeneration based on the mean value derived using Kwok's meniscus scoring system (score 0-24) (power = 0.8, α = 0.05), as determined in our previous studies [19].…”

“…Many studies have focused on the contributions of canonical IKK family members, IKKα, IKKβ and IKKγ, to articular cartilage pathology and their potential roles in treating OA due to their inhibitory effects [15][16][17][18]. In recent ndings, a non-canonical IKK, IKKε was highlighted to contribute to the pathogenesis of OA by promoting NF-κB signaling-mediated chondrocyte catabolism, and therefore the IKKε inhibitor BAY-985 emerges as a promising candidate for modifying the progression of OA [19]. However, their functions of these IKK family members in meniscal degeneration have not been investigated at all.…”