A MATRIX METALLOPROTEINASE PROENZYME ACTIVATOR PRODUCED BY ARTICULAR-CARTILAGE

Matrix metalloproteinases (MMPs) are involved in connective tissue tur nover under physiological and pathological conditions. MMP activity is regulated by the requirement for zymogen activation. This report desc ribes a proMMP-3 activator produced by articular cartilage. The activa tor initiates a step-wise processing of proMMP-3 to generate an array of active species. Sequencing of activation intermediates demonstrated cleavage on the NH2-terminal side of certain basic residues in the MM P-3 propeptide. Metal ion chelators inhibited activator-dependent prot eolysis, and activity was restored by low levels of ZnCl2. These catal ytic properties suggest similarity to members of the insulinase superf amily of metalloendopeptidases with in vitro specificity for single ar ginine or paired basic processing sites in a variety of prohormones. D ibasic sites also exist in the propeptides of several MMPs including p roMMP-3. This is the first report that cartilage produces a potent MMP proenzyme activator, opening the possibility of a novel intrinsic act ivation pathway for catabolic processes in this avascular tissue. (C) 1998 Academic Press.