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

研究成果: ジャーナルへの寄稿学術誌査読


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. (Figure presented.).

ジャーナルArthritis and Rheumatology
出版ステータス出版済み - 6月 2023

!!!All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • リウマチ学
  • 免疫学


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