Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA expression in the synovial membrane and synovial fibroblasts of patients with rheumatoid arthritis

Arthritis Rheum. 1999 Jul;42(7):1517-27. doi: 10.1002/1529-0131(199907)42:7<1517::AID-ANR27>3.0.CO;2-G.


Objective: To study the localization and cell type-specific expression of collagenase 3 messenger RNA (mRNA) in the synovial membrane, its regulation in primary synovial fibroblasts, and the correlation with systemic markers of inflammation and radiographic damage in rheumatoid arthritis (RA).

Methods: The expression of collagenase 3 mRNA was characterized by Northern blot analysis, reverse transcriptase-polymerase chain reaction, and in situ hybridization. Immunohistochemical detection of cell type-specific antigens was used in combination with in situ hybridization of collagenase 3 mRNA to characterize the cellular origin of collagenase 3 mRNA expression.

Results: Collagenase 3 mRNA was detected in synovial membrane specimens of 21 of 36 RA patients (58%) and correlated with an increase in erythrocyte sedimentation rate (P<0.05) and C-reactive protein levels (P<0.005). Collagenase 3 mRNA was localized in fibroblast-like cells of the lining and sublining layers, and at the synovial membrane-cartilage interface. Four of 10 primary synovial fibroblast cell cultures showed basal expression of collagenase 3 mRNA, which was stimulated 2-4-fold upon interleukin-1beta or tumor necrosis factor alpha treatment and, in contrast to interstitial collagenase mRNA, 5-10-fold by increasing the intracellular level of cAMP. The stimulation by cAMP analogs was completely abolished by protein kinase A inhibitors.

Conclusion: Some RA patients show collagenase 3 mRNA expression in the synovial membrane, which correlates with elevated levels of systemic markers of inflammation in these patients. In synovial fibroblasts, the expression of collagenase 3 and interstitial collagenase mRNA is differentially regulated by distinct protein kinase signal transduction pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adenylyl Cyclases / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / enzymology*
  • Arthritis, Rheumatoid / pathology*
  • Bucladesine / pharmacology
  • Cells, Cultured
  • Colforsin / pharmacology
  • Collagenases / genetics*
  • Cyclic AMP / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Fibroblasts / chemistry
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Humans
  • In Situ Hybridization
  • Male
  • Matrix Metalloproteinase 13
  • Middle Aged
  • Phosphodiesterase Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • Radiography
  • Synovial Membrane / cytology*
  • Synovial Membrane / metabolism*


  • Phosphodiesterase Inhibitors
  • RNA, Messenger
  • Colforsin
  • Bucladesine
  • Cyclic AMP
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Adenylyl Cyclases
  • 1-Methyl-3-isobutylxanthine