Rheumatology Advance Access published online on July 5, 2005
Rheumatology, doi:10.1093/rheumatology/kei006
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1 Department of Internal Medicine, Division of Rheumatology, University of Florence, Florence, Italy
* To whom correspondence should be addressed. Objective. Extracellular fibrinolysis, controlled by the cell-associated fibrinolytic system (urokinase plasminogen activator, uPA; uPA receptor, uPAR; plasminogen activator inhibitor type-1, PAI-1), is involved in cartilage damage generation and in rheumatoid arthritis (RA) synovitis. Since steroids reduce the rate of radiological progression of RA, we planned to evaluate in healthy and RA synoviocytes the effects of the steroid deflazacort on uPA, uPAR and PAI-1 expression, and subsequent phenotypic modifications in terms of uPA/uPAR-dependent invasion and proliferation. Methods. uPA, uPAR and PAI-1 levels were studied by ELISA, RT-PCR (uPAR) and zymography (uPA) in synoviocytes from four RA patients and four healthy controls. Chemoinvasion was assessed by the Boyden chamber invasion assay, using Matrigel as the invasion substrate. Proliferation was evaluated by cell counting. Both invasion and proliferation were measured upon treatment with deflazacort 5 µM with or without parallel stimulation with uPA 500 ng/ml or in the presence of monoclonal anti-uPA and anti-uPAR antibodies. Results. Invasion and proliferation of RA synoviocytes require a proper functional balance of the fibrinolytic system. Both deflazacort and monoclonal antibodies against uPA and uPAR reduced expression and activity of the system, thus inhibiting invasion and proliferation. In RA synoviocytes, deflazacort induced higher PAI-1 and lower uPA and uPAR levels, as well as a decrease in uPA enzymatic activity. The levels of uPAR mRNA were concomitantly reduced, as was uPA-induced chemoinvasion. All these effects were also shown in controls, though to a lesser extent. Conclusions. Deflazacort might control RA synovial proliferation and invasion by differential modulation of single members of the fibrinolytic system.
Received October 14, 2004
Accepted May 24, 2005
Original Papers
Deflazacort modulates the fibrinolytic pattern and reduces uPA-dependent chemioinvasion and proliferation in rheumatoid arthritis synoviocytes
2 Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy
3 Institute of Clinical Medicine, Hematology and Clinical Immunology, University of Ancona, Ancona, Italy
4 Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy
5 Medical Direction, Laboratori Guidotti S.p.a., Pisa, Italy
M. Matucci Cerinic, E-mail: cerinic{at}unifi.it
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