PMID:11435459

Citation	Han, Z, Boyle, DL, Chang, L, Bennett, B, Karin, M, Yang, L, Manning, AM and Firestein, GS (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108:73-81
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.
Links	PubMed PMC209341 Online version:10.1172/JCI12466
Keywords	Activating Transcription Factor 2; Animals; Anthracenes/pharmacology; Arthritis, Experimental/enzymology; Arthritis, Experimental/pathology; Cells, Cultured/drug effects; Cells, Cultured/enzymology; Collagenases/biosynthesis; Collagenases/genetics; Cyclic AMP Response Element-Binding Protein/metabolism; Enzyme Induction/drug effects; Enzyme Inhibitors/pharmacology; Flavonoids/pharmacology; Interleukin-1/antagonists & inhibitors; Interleukin-1/pharmacology; Isoenzymes/antagonists & inhibitors; Isoenzymes/genetics; Isoenzymes/physiology; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System; Matrix Metalloproteinase 13; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 10; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/physiology; Phosphorylation/drug effects; Protein Processing, Post-Translational/drug effects; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Protein-Tyrosine Kinases/antagonists & inhibitors; Protein-Tyrosine Kinases/genetics; Protein-Tyrosine Kinases/physiology; Proto-Oncogene Proteins c-jun/metabolism; RNA, Messenger/biosynthesis; Rats; Rats, Inbred Lew; Synovial Membrane/cytology; Transcription Factor AP-1/deficiency; Transcription Factor AP-1/physiology; Transcription Factors/metabolism; p38 Mitogen-Activated Protein Kinases
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:MK08	involved_in	GO:0006954: inflammatory response	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.