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

Taisuke Uchida, Yukio Akasaki, Takuya Sueishi, Ichiro Kurakazu, Masakazu Toya, Masanari Kuwahara, Ryota Hirose, Yuki Hyodo, Hidetoshi Tsushima, Martin K Lotz, Yasuharu Nakashima

Arthritis & rheumatology (Hoboken, N.J.) 2023 Jun

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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. 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. 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. 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. © 2022 American College of Rheumatology.

Citation

Taisuke Uchida, Yukio Akasaki, Takuya Sueishi, Ichiro Kurakazu, Masakazu Toya, Masanari Kuwahara, Ryota Hirose, Yuki Hyodo, Hidetoshi Tsushima, Martin K Lotz, Yasuharu Nakashima. Promotion of Knee Cartilage Degradation by IκB Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models. Arthritis & rheumatology (Hoboken, N.J.). 2023 Jun;75(6):937-949