c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis

J Clin Invest. 2001 Jul;108(1):73-81. doi: 10.1172/JCI12466.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Activating Transcription Factor 2
  • Anthracenes
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Flavonoids
  • Interleukin-1
  • Isoenzymes
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • Transcription Factors
  • pyrazolanthrone
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinase 9
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • Map3k1 protein, mouse
  • Collagenases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Mmp13 protein, rat
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one