RelA is required for IL-1β stimulation of Matrix Metalloproteinase-1 expression in chondrocytes

Objective: Interleukin-1 beta (IL-1 beta) stimulates collagenase-1 (Matrix Metalloproteinase-1 (MMP-1)) expression in articular chondrocytes, leading to cleavage of type II collagen and irreversible cartilage degradation. The nuclear factor-kappa B (NF-kappa B) pathway is potently activated in IL-1 beta-stimulated cells and has been implicated as an intermediate in MMP-1 gene expression. However, the roles of individual NF-kappa B family members during IL-1 beta-induced MMP-1 gene expression have not been defined. Results: To address the relationship between the NF-kappa B pathway and MMP-1 gene activation in chondrocytes, primary cultured human articular chondrocyte cultures (HAC) and SW-1353 cells were stimulated with IL-1 beta over a 24-h time course and MMP-1, NF-kappa B1, NF-kappa B2 and ReIA gene expression was assayed. IL-1 beta-induced MMP-1 expression was comparable in HAC and SW-1353 cells both temporally and quantitatively. MMP-1 gene expression was mirrored by increases in NF-kappa B gene expression, and inhibition of NF-kappa B nuclear translocation with dominant-negative I kappa B alpha reduced IL-1 beta-dependent MMP-1 gene expression. IL-1 beta activated the NF-kappa B pathway in chondrocytes, both through phosphorylation and transient degradation of I kappa B alpha, as well as through sustained phosphorylation of ReIA. Small inhibitory RNAs (siRNA) specific for ReIA resulted in significant reduction of MMP-1 mRNA, whereas siRNA for NF-kappa B1 and NF-kappa B2 augmented IL-1 beta-induced MMP-1 expression. Conclusions: Our data demonstrate that IL-1 beta activation of the NF-kappa B pathway is required for IL-1 beta induction of MMP-1 in chondrocytes and that ReIA can work independently of NF-kappa B1 or NF-kappa B2 to activate this gene expression program. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.