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Pannus invasion and cartilage degradation in rheumatoid arthritis: Involvement of MMP-3 and interleukin-1b

M.M Ainola, J.A. Mandelin, Mikko P. Liljeström, T.-F. Li, M.V.J. Hukkanen, Y.T. Konttinen

Institute of Biomedicine, Department of Anatomy, University of Helsinki, Helsinki, Finland

ABSTRACT
Objective
Synovial inflammation in rheumatoid arthritis (RA) leads to pannus tissue invasion and destruction of cartilage/bone matrix by proteinases. Our intention was to analyze some of the key matrix metalloproteinases (MMPs) in pannus tissue overlying evolving cartilage erosions in RA.

Methods
Frozen tissue samples of pannus and synovium from advanced RA and synovium from osteoarthritic patients were used for immunohistochemical, western blotting and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of MMP-1, -3, -13 and -14. Synovial fibroblast cultures, stimulated with tumour necrosis factor alpha (TNF-a) and interleukin-1 beta (IL-1b), were analyzed with enzyme-linked immunosorbent assays (ELISA) and quantitative RT-PCR.

Results
MMP-3 was highly expressed in pannus tissue compared with significantly lower expression levels of MMP-1, –13 and –14. In fibroblast cultures IL-1b was a potent stimulus for MMP-3, whereas TNF-a was more potent for MMP-1.

Conclusion
This is the first study to demonstrate quantitatively in real time that MMP-3 mRNA expression is clearly higher in advanced RA pannus tissue compared to parallel RA or osteoarthritic synovium. MMP-3 mRNA levels were also clearly overexpressed in RA pannus compared to MMP-1, -13 and -14. Advanced RA has previously been found to overexpress IL-1b. The high expression of MMP-3 in pannus and IL-1b mediated stimulation of MMP–3 suggest that MMP-3 plays a significant role in the progression of erosions through the proteoglycan-rich cartilage matrix.

Key words
Rheumatoid arthritis, cartilage, inflammation, cytokines, matrix metalloproteinases.

Please address correspondence and reprint requests to: Prof. Yrjö T. Konttinen, Biomedicum Helsinki, P.O. Box 700, 00029 Helsinki University Central Hospital, Finland.
E-mail: yrjo.konttinen@helsinki.fi.