Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate

Matrix Biol. 1999 Aug;18(4):401-12. doi: 10.1016/s0945-053x(99)00030-x.


The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.

MeSH terms

  • Adult
  • Aged
  • Alendronate / pharmacology*
  • Arthritis, Rheumatoid / enzymology*
  • Arthritis, Rheumatoid / pathology
  • Blotting, Western
  • Cartilage, Articular / enzymology*
  • Cartilage, Articular / pathology
  • Collagenases / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Exudates and Transudates / enzymology*
  • Female
  • Humans
  • Immunohistochemistry
  • Interleukin-1 / metabolism
  • Male
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism*
  • Middle Aged
  • Synovial Membrane / enzymology*
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / metabolism


  • Enzyme Inhibitors
  • Interleukin-1
  • Matrix Metalloproteinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases
  • Alendronate