Abstract
Osteoarthritic chondrocytes secrete matrix metalloproteinase-13 (MMP-13) in response to interleukin-1 (IL-1), causing digestion of type II collagen in cartilage. Using chondrocytic cells, we previously determined that IL-1 induced a strong MMP-13 transcriptional response that requires p38 MAPK, JNK and the transcription factor NF-kappaB. Now, we have studied the tissue-specific transcriptional regulation of MMP-13. Constitutive expression of the transcription factor Runx-2 correlated with the ability of a cell type to express MMP-13 and was required for IL-1 induction; moreover, Runx-2 enhanced IL-1 induction of MMP-13 transcription by synergizing with the p38 MAPK signaling pathway. Transiently transfected MMP-13 promoters were not IL-1 inducible. However, -405 bp of stably integrated promoter was sufficient for 5- to 6-fold IL-1 induction of reporter activity and this integrated reporter required the same p38 MAPK pathway as the endogenous gene. Finally, mutation of the proximal Runx binding site and the proximal AP-1 site blunted the transcriptional response to IL-1, and double mutation synergistically decreased reporter activity. In summary, our data suggest that the transcriptional MMP-13 response to IL-1 is controlled by the p38 pathway interacting at the MMP-13 promoter through the tissue-specific transcription factor Runx-2 and the ubiquitous AP-1 transcription factor.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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Chondrocytes / drug effects
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Chondrocytes / metabolism*
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Collagenases / biosynthesis
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Collagenases / genetics*
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Core Binding Factor Alpha 1 Subunit
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Core Binding Factor alpha Subunits
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DNA-Binding Proteins / chemistry
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Drosophila Proteins
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Fibroblasts
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Genes, Reporter / genetics
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Humans
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Imidazoles / pharmacology
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Interleukin-1 / pharmacology*
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 3
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Signaling System / drug effects*
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Matrix Metalloproteinase 13
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Sequence Data
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Mutation / genetics
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NF-kappa B / metabolism
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Neoplasm Proteins*
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Nuclear Proteins
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Promoter Regions, Genetic / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / metabolism
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Pyridines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Response Elements / genetics
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Transcription Factor AP-1 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Up-Regulation / drug effects
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p38 Mitogen-Activated Protein Kinases
Substances
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Core Binding Factor Alpha 1 Subunit
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Core Binding Factor alpha Subunits
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DNA-Binding Proteins
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Drosophila Proteins
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Imidazoles
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Interleukin-1
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NF-kappa B
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Neoplasm Proteins
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Nuclear Proteins
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Pyridines
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RNA, Messenger
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Transcription Factor AP-1
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Transcription Factors
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run protein, Drosophila
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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MAP Kinase Kinase 3
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MAP2K3 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Collagenases
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MMP13 protein, human
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Matrix Metalloproteinase 13
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SB 203580