USP14-mediated IκBα degradation exacerbates NF-κB activation and IL-1β-stimulated chondrocyte dedifferentiation

Osteoarthritis (OA) is an inflammatory joint disease. USP14, a deubiquitinating enzyme critical for ubiquitin-mediated proteasomal protein degradation, is implicated in inflammation regulation. However, its role and mechanism in OA are poorly understood. Here, we report that USP14 is upregulated in OA articular cartilage as well as in chondrocytes treated with IL-1β in vitro. USP14 upregulation depends on NF-κB pathway activation, since inhibition of this pathway by ACHP, a selective inhibitor of IKK-β, abolishes USP14 upregulation. We further show that USP14 in turn exacerbates NF-κB activation through promoting IκBα deubiquitination and degradation. Functionally, USP14 aggravates the dedifferentiation effect of IL-1β on chondrocytes, and NF-κB inhibition remarkably reverses this effect, highlighting an important role of NF-κB in mediating USP14 function. Collectively, our data reveal a previously unidentified feed-forward loop driven by USP14 and NF-κB pathway in promoting the dedifferentiation effect of IL-1β on chondrocytes. This mechanism might offer a useful hint for OA intervention.