A novel approach to measure the contribution of matrix metalloproteinase in the overall net proteolytic activity present in synovial fluids of patients with arthritis |
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Authors: | Nathalie Simard Gilles Boire Artur J de Brum-Fernandes Yves St-Pierre |
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Institution: | INRS-Institut Armand-Frappier, University of Québec, Laval, Québec, Canada. |
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Abstract: | Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful
in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor
the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium
between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the
enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected
from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies,
and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of
proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients
correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations
were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found
in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness
varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity,
and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic
enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest
an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis. |
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