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

by Selleckchem | Sep 10 2023

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.

Comments:

Title: The Role of IKKε in Osteoarthritis Pathogenesis and the Potential of IKKε Inhibition as a Modulatory Treatment

Objective: The objective of this study was to investigate the functional involvement of IκB kinase ε (IKKε) in the pathogenesis of osteoarthritis (OA) and evaluate the effectiveness of IKKε inhibition as a modulatory treatment. The study aimed to determine the expression of IKKε in normal and OA human knee joints, assess the impact of IKKε modulation on OA-related factors in human chondrocytes, and examine the effects of IKKε inhibition in a surgically induced OA mouse model.

Methods:
1. Immunohistochemical analysis: The expression of IKKε protein was analyzed in normal and OA human knee joints using immunohistochemistry.
2. In vitro experiments: Gain- and loss-of-function experiments were performed in human chondrocytes. IKKε expression was knocked down using small interfering RNA (siRNA) in OA chondrocytes, and the effects on OA-related factors were evaluated. Conversely, IKKε overexpression was induced, and the expression of OA-related catabolic mediators was assessed. Western blot analysis was conducted to analyze the phosphorylation of IκBα and p65 in response to IKKε modulation.
3. In vivo experiments: OA was surgically induced in mice, followed by intraarticular injection of BAY-985, an inhibitor of IKKε and TANK-binding kinase 1, into the left knee joint at regular intervals. The mice were evaluated for histologic features of cartilage damage and inflammation associated with OA.

Results:
1. IKKε protein expression: Increased IKKε protein expression was observed in human OA cartilage compared to normal cartilage.
2. In vitro findings: Knockdown of IKKε using siRNA or treatment with BAY-985 resulted in the down-regulation of OA-related factors in human OA chondrocytes. Conversely, IKKε overexpression increased the expression of OA-related catabolic mediators. Western blot analysis confirmed that IKKε overexpression enhanced the phosphorylation of IκBα and p65 in human chondrocytes.
3. In vivo effects: Intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia, potentially mediated through the modulation of NF-κB signaling.

Conclusion: The study findings suggest that IKKε plays a regulatory role in cartilage degradation by mediating a catabolic response through the NF-κB signaling pathway. Therefore, IKKε represents a potential target for the treatment of osteoarthritis. The study also indicates that BAY-985, an IKKε/TANK-binding kinase 1 inhibitor, could be a promising disease-modifying compound for OA. Further research and development of IKKε inhibitors may offer therapeutic opportunities for osteoarthritis management.