Abstract
Mitogen-activated protein kinase (MAPK) cascades are involved in inflammation and tissue destruction in rheumatoid arthritis (RA). In particular, c-Jun N-terminal kinase (JNK) is highly activated in RA fibroblast-like synoviocytes and synovium. However, defining the precise function of this kinase has been difficult because a selective JNK inhibitor has not been available. We now report the use of a novel selective JNK inhibitor and JNK knockout mice to determine the function of JNK in synoviocyte biology and inflammatory arthritis. The novel JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) completely blocked IL-1--induced accumulation of phospho-Jun and induction of c-Jun transcription in synoviocytes. Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125. In contrast, complete inhibition of p38 had no effect, and ERK inhibition had only a modest effect. The essential role of JNK was confirmed in cultured synoviocytes from JNK1 knockout mice and JNK2 knockout mice, each of which had a partial defect in IL-1--induced AP-1 activation and collagenase-3 expression. Administration of SP600125 modestly decreased the rat paw swelling in rat adjuvant-induced arthritis. More striking was the near-complete inhibition of radiographic damage that was associated with decreased AP-1 activity and collagenase-3 gene expression. Therefore, JNK is a critical MAPK pathway for IL-1--induced collagenase gene expression in synoviocytes and in joint arthritis, indicating that JNK is an important therapeutic target for RA.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Animals
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Anthracenes / pharmacology*
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Arthritis, Experimental / enzymology*
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Arthritis, Experimental / pathology
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Collagenases / biosynthesis*
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Collagenases / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology*
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Flavonoids / pharmacology
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / physiology
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Signaling System*
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Matrix Metalloproteinase 13
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / physiology*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology*
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / biosynthesis
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Rats
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Rats, Inbred Lew
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Synovial Membrane / cytology
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Transcription Factor AP-1 / deficiency
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Transcription Factor AP-1 / physiology
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Transcription Factors / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Activating Transcription Factor 2
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Anthracenes
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Flavonoids
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Interleukin-1
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Isoenzymes
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Transcription Factor AP-1
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Transcription Factors
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pyrazolanthrone
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinase 9
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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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, mouse
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Collagenases
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse
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Mmp13 protein, rat
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one