Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator
Werb, Z.; Mainardi, C.L.; Vater, C.A.; Harris, E.D.
New England Journal of Medicine 296(18): 1017-1023
ISSN/ISBN: 0028-4793 PMID: 66627 DOI: 10.1056/nejm197705052961801
To elucidate the mechanism of synovial damage in rheumatoid arthritis, the activation of latent collagenases released from adherent rheumatoid synovial cells in culture was studied. Latent enzyme was not complexed with .alpha.2 macroglobulin, the principal proteinase inhibitor in serum, and could be activated by trypsin in the presence of .alpha.2 macroglobulin if sufficient proteinase was added to saturate inhibitor. Latent collagenase bound half as effectively to collagen fibrils as active enzyme. Plasmin was a 3-fold better activator of latent enzyme than trypsin and could be generated by addition of plasminogen to synovial-cell cultures. Production of both collagenase and plasminogen activator was inhibited by dexamethasone (10-9 M). These studies emphasize the importance of control of activation in regulating collagenase activity. It is likely that rheumatoid synovium produces both latent collagenase and plasminogen activator; plasmin is activated from its zymogen, plasminogen, present in inflamed tissues, and in turn activates collagenase.