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

Z Han1, D L Boyle, L Chang

  • 1Division of Rheumatology, Allergy and Immunology, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA.

The Journal of Clinical Investigation
|July 4, 2001
PubMed

Insights

A novel selective inhibitor of c-Jun N-terminal kinase (JNK) and JNK knockout mice reveal JNK

Area of Science:

  • Molecular Biology
  • Immunology
  • Rheumatology

Background:

  • Mitogen-activated protein kinase (MAPK) pathways, including c-Jun N-terminal kinase (JNK), are implicated in rheumatoid arthritis (RA) pathogenesis.
  • JNK is highly activated in RA fibroblast-like synoviocytes and synovium, but its precise role has been unclear due to the lack of selective inhibitors.

Purpose of the Study:

  • To elucidate the function of JNK in synoviocyte biology and inflammatory arthritis using a novel selective JNK inhibitor and JNK knockout models.

Main Methods:

  • Utilized the novel selective JNK inhibitor SP600125 and JNK1/JNK2 knockout mice.
  • Assessed IL-1-induced activation of transcription factors (e.g., phospho-Jun, AP-1) and collagenase gene expression in synoviocytes.
  • Evaluated the effects of SP600125 on paw swelling and radiographic damage in a rat adjuvant-induced arthritis model.

Main Results:

  • SP600125 completely inhibited IL-1-induced phospho-Jun accumulation, c-Jun transcription, AP-1 binding, and collagenase mRNA in synoviocytes.
  • JNK1 and JNK2 knockout synoviocytes showed partial defects in IL-1-induced AP-1 activation and collagenase-3 expression.
  • SP600125 administration reduced paw swelling and significantly inhibited radiographic damage in a rat arthritis model.

Conclusions:

  • JNK is a critical MAPK pathway mediating IL-1-induced collagenase gene expression in synoviocytes.
  • Targeting JNK represents a promising therapeutic strategy for managing rheumatoid arthritis and its associated joint destruction.

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