Alleviation of Murine Osteoarthritis by Cartilage-Specific Deletion of IκBζ

Objective. I kappa B zeta, an atypical I kappa B family member, regulates gene expression in the nucleus as a transcriptional cofactor. Although I kappa B has been extensively studied in the immune system, its specific roles in osteoarthritis (OA) are currently unknown. The objective of this study was to investigate the potential role of I kappa B zeta in chondrocyte catabolism and OA pathogenesis. We also determined the molecular mechanism underlying its relationship to the transcription factor NF-kappa B. Methods. We determined expression levels of I kappa B zeta in mouse chondrocytes treated with interleukin-1 beta (IL-1 beta), in human OA cartilage, and in mouse experimental OA cartilage. Adenovirus-mediated overexpression and small interfering RNA knockdown of I kappa B zeta were performed to determine the impact of I kappa B zeta on catabolic gene expression in vitro. Cartilage-specific I kappa B zeta-transgenic and -knockout mice were generated and used for in vivo studies. Experimental and spontaneous OA were induced by surgical destabilization of the medial meniscus and by aging, respectively. Coimmunoprecipitation assay was used to examine the association between I kappa B zeta and NF-kappa B subunits. Results. I kappa B zeta was highly up-regulated in chondrocytes in response to IL-1 beta and in OA cartilage of human and mouse knee joints. Overexpression of I kappa B zeta in chondrocytes promoted spontaneous OA development by activating chondrocyte catabolism. Genetic ablation of I kappa B zeta in chondrocytes abolished catabolic gene induction by IL-1 beta and protected against the development of experimental OA. I kappa B zeta formed complexes with NF-kappa B members to regulate catabolic factor expression. Conclusion. These findings demonstrate a critical role for I kappa B zeta in OA pathogenesis. Inhibition of I kappa B zeta function might be an effective therapeutic approach for OA treatment.