Title: Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3.
Authors: Mengshol, J A; Vincenti, M P; Coon, C I; Barchowsky, A; Brinckerhoff, C E
Published In Arthritis Rheum, (2000 Apr)
Abstract: OBJECTIVE: To examine the mechanism of interleukin-1 (IL-1)-induced collagenase 3 (matrix metalloproteinase 13 [MMP-13]) gene expression in cultured chondrocytes for the purpose of better understanding how the gene is induced in these cells, and how it contributes to cartilage degradation in osteoarthritis. METHODS: The transcriptional and posttranscriptional responses of the MMP-13 gene to IL-1 were assessed first. Then, direct inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and a constitutive repressor of nuclear factor kappaB (NF-kappaB) were used to assess the role of each pathway in IL-1-mediated induction of MMP-13. RESULTS: We found that IL-1 induction of MMP-13 requires p38 activity, c-Jun N-terminal kinase (JNK) activity and NF-kappaB translocation. These results suggest that both NF-kappaB and activator protein 1 transcription factors are necessary for IL-1 induction of MMP-13. We also compared the signaling pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in articular chondrocytes and chondrosarcoma cells and found that IL-1 induction of MMP-1 requires different pathways from those required by MMP-13. In chondrosarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of the extracellular signal-regulated kinase pathway) and does not require JNK or NF-kappaB. 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, and NF-kappaB are required for IL-1 induction of MMP-13. The results also highlight the differential requirements for signaling pathways in the induction of MMP-1 and MMP-13. Additionally, they demonstrate that induction of MMP-1 by IL-1 in chondrocytic cells depends on unique combinations of signaling pathways that are cell type-specific.
PubMed ID: 10765924
MeSH Terms: Chondrocytes/enzymology; Collagenases/genetics*; Enzyme Induction/drug effects; Gene Expression Regulation; Humans; Interleukin-1/pharmacology*; Interstitial Collagenase/biosynthesis; Interstitial Collagenase/genetics; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/physiology; Mitogen-Activated Protein Kinases/pharmacology*; NF-kappa B/pharmacology*; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Transfection; p38 Mitogen-Activated Protein Kinases