Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator.
To elucidate the mechanism of synovial damage in rheumatoid arthritis, we studied the activation of latent collagenases released from adherent rheumatoid synovial cells in culture. Latent enzyme was not complexed with alpha2 macroglobulin, the prinicpal proteinase inhibitor in serum, and could be activated by trypsin in the presence of alpha2 macroglobulin if sufficient proteinase was added to saturate inhibitor. Latent collagenase bound half as effectively to collagen fibrils as active enzyme. Plasmin was a threefold 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 in importance of control of activation in regulation 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.
D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D003012:Microbial Collagenase / Q000096:biosynthesis / Q000378:metabolism*; D010958:Plasminogen / Q000096:biosynthesis; D010960:Plasminogen Activators / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D013583:Synovial Membrane / Q000166:cytology / Q000201:enzymology*; D013585:Synovitis / Q000201:enzymology; D014357:Trypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
D011453:Prostaglandins; D000511:alpha-Macroglobulins; D003907:Dexamethasone; D010958:Plasminogen; D010960:Plasminogen Activators; D014357:Trypsin; D005341:Fibrinolysin; D003012:Microbial Collagenase