PLASMINOGEN MODULATION OF IL-1-STIMULATED DEGRADATION IN BOVINE AND HUMAN ARTICULAR-CARTILAGE EXPLANTS - THE ROLE OF THE ENDOGENOUS INHIBITORS - PAI-1, ALPHA(2)-ANTIPLASMIN, ALPHA(1)-PI, ALPHA(2)-MACROGLOBULINAND TIMP

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity o f matrix metalloproteinases and cartilage degradation related to non-i nflammatory joint disease, like osteoarthritis. An interleukin-1-induc ed model of degradation using [S-35]-labeled bovine and human articula r cartilage explants was utilized. One goal of these studies was to co mpare the responses of bovine and human articular cartilage. Degradati on was not inhibited by alpha(1)-PI, PAI-1, alpha(2)-macroglobulin, al pha(2)-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of h uman plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under the se conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade wh ere activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromel ysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha(2)-antiplasmin, alpha(1)-PI and alpha(2)-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An exper iment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants wer e stimulated with interleukin-1 alone. Addition of human plasminogen ( at physiologically relevant concentrations) resulted in significant de gradation, which was inhibited in the same manner as in bovine explant s, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much mo re efficient in human explants, indicating the limited participation o f human plasmin in the degradation of human cartilage. Although specul ative, it is possible that in vivo, cartilage degradation could be pro moted not only by TIMP/MMP imbalance, but also accelerated by decrease d levels of certain serpins in synovial fluid (e.g. PAIs, alpha(2)-ant iplasmin and alpha(1)-PI).