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Characterisation of the cell type-specificity of collagenase 3 mRNA expression in comparison with membrane type 1 matrix metalloproteinase and gelatinase A in the synovial membrane in rheumatoid arthritis

P K Petrow¹, D Wernicke², C Schulze Westhoff², K M Hummel³, R Bräuer¹, J Kriegsmann⁴, E Gromnica-Ihle⁵, R E Gay⁶, S Gay⁶

¹ Institute of Pathology, University of Jena, Germany
² Max-Delbrück-Centre for Molecular Medicine, Berlin-Buch, Germany
³ Department of Nephrology and Rheumatology, University of Göttingen, Germany
⁴ Institute of Pathology, University of Mainz, Germany
⁵ Clinic of Rheumatology, Berlin-Buch, Germany
⁶ University Hospital of Zürich, Zürich, Switzerland

Correspondence to:
Correspondence to:
Dr P K Petrow, Institute of Pathology, University of Jena, Ziegelmühlenweg 1, D-07740 Jena, Germany;
peterpetrow{at}excite.com

Objective: To study the pattern and cell type-specificity of collagenase 3, membrane-type 1 matrix metalloproteinase (MT1-MMP), and gelatinase A mRNA expression in the synovial membrane in rheumatoid arthritis (RA).

Methods: The mRNA expression of collagenase 3, MT1-MMP, and gelatinase A was characterised by northern blot analysis, reverse transcriptase-polymerase chain reaction, and in situ hybridisation. In situ hybridisation was performed in combination with the immunohistochemical detection of cell type-specific antigens.

Results: Synovial membrane specimens from 19 of 21 patients with RA expressing collagenase 3 mRNA were positive for MT1-MMP and gelatinase A mRNA. In control samples from patients without destructive inflammatory joint diseases collagenase 3 mRNA was not expressed and only in two of seven cases was a coexpression of MT1-MMP and gelatinase A mRNA detected. Fibroblast-like cells of the synovial membrane were found to be the predominant source of collagenase 3, MT1-MMP, and gelatinase A mRNA expression in lining and sublining layers as well as at the synovial membrane-cartilage interface. Additionally, the expression of MT1-MMP mRNA was detected in endothelial cells. Collagenase 3 mRNA expression was found in about 5% of CD68 positive macrophages.

Conclusions: Collagenase 3 mRNA is expressed simultaneously with MT1-MMP and gelatinase A mRNA in fibroblast-like cells of the synovial membrane in RA. These results suggest (a) a broad extracellular proteolytic potential of fibroblast-like cells and (b) an important role of cell surface associated procollagenase 3 activation by MT1-MMP and gelatinase A for cartilage degradation by invading fibroblast-like cells.

Keywords: synovial fibroblasts; matrix metalloproteinases; cartilage degradation

Abbreviations: APAAP, alkaline phosphatase-anti-alkaline phosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mAb, monoclonal antibody; MT1-MMP, membrane-type 1 matrix metalloproteinase; NBT/BCIP, nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indolylphosphate; RA, rheumatoid arthritis; RT-PCR, reverse transcriptase-polymerase chain reaction

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