Interferon-gamma inhibits interleukin-1beta-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis

Arthritis Res Ther. 2010;12(2):R49. doi: 10.1186/ar2960. Epub 2010 Mar 22.

Abstract

Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-gamma (IFN-gamma) during early inflammatory arthritis.

Methods: We studied IFN-gamma's capacity to modulate interleukin-1beta (IL-1beta) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)).

Results: IFN-gamma modulated IL-1beta driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-gamma did not affect IL-1beta induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-gamma reduced IL-1beta expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA.

Conclusions: Early therapeutic intervention with IFN-gamma may be critical to orchestrate tissue-protective responses during inflammatory arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Animals, Newborn
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / enzymology
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / pathology
  • Cartilage, Articular / drug effects*
  • Cartilage, Articular / metabolism
  • Cattle
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Coculture Techniques
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Interferon-gamma / pharmacology*
  • Interleukin-1beta / metabolism
  • Male
  • Matrix Metalloproteinases / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Middle Aged
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism

Substances

  • Interleukin-1beta
  • Interferon-gamma
  • Matrix Metalloproteinases