Matrix metalloproteinases, IL-6, and nitric oxide in rat antigen-induced arthritis.
OBJECTIVE
Degradation of extracellular matrix by matrix metalloproteinases (MMPs) is believed to be important in processes leading to the progressive destruction of joints in rheumatoid arthritis (RA). We used the model of antigen-induced arthritis (AIA) to study MMP activity and the influence of cytokines on their expression by synoviocytes.


METHODS
Procedures used were: mBSA-induced arthritis in rats; investigation of synovial fluids and supernatants of cultured synoviocytes at different time points during AIA; estimation of total MMP activities by fluorescence assay; zymographic investigations; IL-6 bioassay with B9 cells; nitric oxide (NO) estimation.


RESULTS
Total MMP activity in the synovial fluids of arthritic joints was higher than in the contralateral joints or in the joints of untreated control animals. The maximum was noted between day 7 and day 14 after arthritis induction. Cultured synoviocytes, prepared at different time points after arthritis induction, secreted MMPs into the media with a maximum time lapse of 14 days after arthritis induction. TNF-alpha increased the total MMP activity released. Moreover, TNF-alpha as well as IL-1 beta induced the expression of MMP9. Finally, TNF-alpha increased the levels of IL-6 and NO in the supernatants of synoviocytes; the extent of stimulation was dependent on the course of AIA.


CONCLUSIONS
Different MMPs are synthesized in varying concentrations during the course of rat AIA. Cytokines such as TNF-alpha and IL-1 beta differentially influence the activity and expression of MMPs in cultured synoviocytes. The participation of MMPs in tissue degradation during the course of arthritis may be of importance for the development of new therapeutic strategies.
Mentzel
K
K
Institute of Pathology, Friedrich Schiller University Jena, Germany.
Bräuer
R
R
D000818:Animals; D016918:Arthritis, Reactive / Q000201:enzymology* / Q000276:immunology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005780:Gelatin / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013582:Synovial Fluid / Q000737:chemistry / Q000201:enzymology; D013583:Synovial Membrane / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005780:Gelatin; D008666:Metalloendopeptidases