STROMELYSIN-1 (MMP-3)-INDEPENDENT GELATINASE EXPRESSION AND ACTIVATION IN MICE

A potential physiological role of stromelysin-1 (MMP-8) in the express ion or activation of gelatinase A (MMP-2) or gelatinase B (MMP-9) in t he wall of injured arteries was studied with the use of homozygous MMP -8-deficient (MMP3(-/-)) mice. One week after perivascular electric in jury of the carotid or femoral artery in wild-type (MMP-3(+/+)) or MMP 3(-/-) mice, 70 kD and 65 kD proMMP-2 levels were enhanced by twofold to fourfold, with corresponding increases of 20- to 40-fold for active 61 kD and 58 kD MMP-2, and of 10- to 80-fold for 94 kD proMMP-9, Acti ve MMP-2 species represented approximately one third of the total MMP- 2 concentration for both MMP-3(+/+) and MMP-3(-/-) mice. Active 83 kD MMP-9 was not detected in noninjured carotid or femoral arteries, wher eas one week after injury its contribution to the total MMP-9 level wa s 11% to 18% for MMP-3(+/+) and MMP-3(-/-) mice. Immunostaining of art erial sections confirmed enhanced expression of both MMP-2 and MMP-9 a fter vascular injury. Double immunostaining showed colocalization of M MP-9 with macrophages in the adventitia, whereas MMP-2 was also detect ed mainly in the adventitia but failed to colocalize with smooth muscl e cells. Cell culture experiments confirmed comparable ratios of activ e versus latent MMP-2 in skin fibroblasts and smooth muscle cells deri ved from MMP-3(+/+) and MMP-3(-/-) mice. Addition of plasmin(ogen) did not significantly affect activation of proMMP-2, In MMP-3(+/+) and MM P-3(-/-) macrophages, comparable levels of 94 kD proMMP-9 were detecte d, and plasmin(ogen)mediated conversion to 83 kD MMP-9 was obtained in both genotypes, These data thus indicate that proMMP-2 activation may occur via a plasmin-and MMP-3-independent mechanism, whereas plasmin can directly activate proMMP-9 via a MMP-3-independent mechanism. (C) 1998 by The American Society of Hematology.