Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappa B - Differential regulation of collagenase 1 and collagenase 3

Objective. To examine the mechanism of interleukin-1 (IL-1)-induced collage nase 3 (matrix metalloproteinase 13 [MMP-13]) gene expression in cultured c hondrocytes for the purpose of better understanding how the gene is induced in these cells, and how it contributes to cartilage degradation in osteoar thritis. Methods. The transcriptional and posttranscriptional responses of the MMP-1 3 gene to IL-1 were assessed first. Then, direct inhibitors of mitogen-acti vated protein kinase (MAPK) signaling pathways and a constitutive repressor of nuclear factor kappa B (NF-kappa B) were used to assess the role of eac h pathway in IL-1-mediated induction of MMP-13. Results. We found that IL-1 induction of MMP-13 requires p38 activity, c-Ju n N-terminal kinase (JNK) activity and NF-kappa B translocation. These resu lts suggest that both NF-kappa B and activator protein 1 transcription fact ors are necessary for IL-1 induction of MMP-13. We also compared the signal ing pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in artic ular chondrocytes and chondrosarcoma cells and found that IL-1 induction of MMP-1 requires different pathways from those required by MMP-13. In chondr osarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of t he extracellular signal-regulated kinase pathway) and does not require JNK or NF-kappa B. In articular chondrocytes, inhibition of MEK had no effect, while inhibition of p38 gave variable results. Conclusion. These studies demonstrate, for the first time, that p38, JNK, a nd NF-kappa B are required for IL-1 induction of MMP-13. The results also h ighlight the differential requirements for signaling pathways in the induct ion of MMP-1 and MMP-13. Additionally, they demonstrate that induction of M MP-1 by IL-1 in chondrocytic cells depends on unique combinations of signal ing pathways that are cell type-specific.