Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy

Arthritis Rheum. 2004 Sep;50(9):2942-53. doi: 10.1002/art.20477.


Objective: To investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in spondylarthropathy (SpA) synovitis.

Methods: Paired samples of synovial biopsy tissue as well as serum and synovial fluid (SF) from 41 patients with SpA and 20 patients with rheumatoid arthritis (RA) and serum samples from 20 healthy controls were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay for the presence of MMPs 1, 2, 3, and 9 and TIMPs 1 and 2. In addition, sera from 16 patients with ankylosing spondylitis (AS) and peripheral synovitis and 17 patients with AS and exclusively axial involvement were analyzed. An additional cohort of SpA patients was analyzed at baseline and after 12 weeks of infliximab treatment.

Results: Staining for MMPs and TIMPs showed a cellular and interstitial pattern in the synovial lining and sublining layers that was similar between the RA and SpA patients. Involvement of MMPs and TIMPs in SpA synovitis was suggested by the correlation with cellular infiltration, vascularization, and cartilage degradation. Higher serum levels of MMPs 3 and 9 were revealed in SpA and RA patients as compared with healthy controls. Production of MMP-3, but not MMP-9, in the serum reflected the presence of peripheral synovitis, as indicated by 1) the correlation between serum levels, SF levels (which were 1,000-fold higher than the serum levels), and synovial expression of MMP-3, 2) the increased levels of MMP-3 in AS patients with peripheral disease and not exclusively axial involvement, and 3) the correlation of serum and SF MMP-3 with parameters of synovial, but not systemic, inflammation. The modulation of the MMP/TIMP system by tumor necrosis factor alpha (TNFalpha) blockade was confirmed by the down-regulation of all MMPs and TIMPs in the synovium and a pronounced and rapid decrease of serum MMP-3.

Conclusion: MMPs and TIMPs are highly expressed in SpA synovitis and mirror both the inflammatory and tissue-remodeling aspects of the local disease process. Serum MMP-3, originating from the inflamed joint, represents a valuable biomarker for peripheral synovitis. Modulation of the MMP/TIMP system by infliximab could contribute to the antiinflammatory and tissue-remodeling effects of TNFalpha blockade in SpA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal / pharmacology
  • Antirheumatic Agents / pharmacology
  • Arthritis, Rheumatoid / immunology
  • Cohort Studies
  • Down-Regulation / immunology
  • Female
  • Humans
  • Infliximab
  • Male
  • Matrix Metalloproteinases / analysis
  • Matrix Metalloproteinases / biosynthesis
  • Matrix Metalloproteinases / drug effects
  • Matrix Metalloproteinases / immunology*
  • Middle Aged
  • Spondylarthropathies / immunology*
  • Spondylitis, Ankylosing / immunology
  • Synovial Fluid / chemistry
  • Synovial Fluid / immunology
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology
  • Synovitis / immunology*
  • Tissue Inhibitor of Metalloproteinases / analysis
  • Tissue Inhibitor of Metalloproteinases / biosynthesis
  • Tissue Inhibitor of Metalloproteinases / drug effects
  • Tissue Inhibitor of Metalloproteinases / immunology*
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / immunology


  • Antibodies, Monoclonal
  • Antirheumatic Agents
  • Tissue Inhibitor of Metalloproteinases
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Matrix Metalloproteinases