ACTIVATION OF HUMAN INTERSTITIAL PROCOLLAGENASE THROUGH DIRECT CLEAVAGE OF THE LEU(83)-THR(84) BOND BY MAST-CELL CHYMASE

In inflamed tissue sites characterized by on-going matrix degradation, the matrix metalloproteinases are secreted as latent precursors which are capable of proteolysis only after extracellular activation. Such areas often contain locally increased numbers of mast cells capable of releasing complexes between heparin proteoglycans and fully active en dopeptidases with either tryptic (tryptase) or both tryptic and chymot ryptic (chymase) activity. We have examined the ability of purified hu man skin chymase to activate human interstitial procollagenase (matrix metalloproteinase-1) in the absence and presence of heparin, the phys iologic associate of chymase. Our studies indicate that chymase activa tes procollagenase in a time- and concentration-dependent manner. Hepa rin was found to increase markedly the rate at which chymase activates procollagenase both by accelerating the cleavage of procollagenase an d also by preventing its further degradation. Moreover, we found that chymase activates procollagenase directly by cleaving the Leu(83)-Thr( 84) bond, without formation of any intermediate species. This is a nov el mechanism for procollagenase activation, which contrasts sharply wi th the activation mechanisms of other activators studied so far. The a bility of chymase to activate procollagenase suggests that chymase pla ys an active role in matrix degradation at tissue sites where mast cel ls coexist with extracellular procollagenase.