Molecular interactions between the plasminogen/plasmin and matrix metalloproteinase systems

Circumstantial evidence suggests an important role of the fibrinolytic (pla sminogen/plasmin) and matrix metalloproteinase (MMP) systems in biological processes involving (extra)cellular proteolysis and matrix degradation. The availability of mice with inactivation of main components of both systems has allowed to study directly the interactions between both systems and the ir biological role. In purified system, MMP-9 (stromelysin-1) specifically hydrolyzes plasminog en and urokinase-type plasminogen activator (u-PA), thereby removing the ce llular binding domains from both proteins. In the presence of cells, MMP-3 may downregulate cell-associated plasmin activity by decreasing the amount of activatible plasminogen, without affecting cell-bound u-PA activity. During neointima formation after vascular injury in gene-deficient mice, ex pression of MMP-2 and MMP-9 (gelatinase A and B) is strongly enhanced, inde pendently of the presence or absence of plasminogen or of the physiological plasminogen activators. Activation of proMMP-2 occurs independently of pla smin, whereas proMMP-9 activation occurs via plasmin-dependent as well as p lasmin-independent mechanisms. The temporal and topographic expression patt erns of MMP-2, MMP-3, MMP-9, MMP-12 (metalloelastase) and MMP-13 (collagena se) establish a potential role in neointima formation. This is further subs tantiated by the finding that neointima formation after vascular injury is significantly enhanced in mice with deficiency of TIMP-1, a main physiologi cal MMP inhibitor. Atherosclerosis models in gene-deficient mice suggest an important role of u-PA in the structural integrity of the atherosclerotic vessel wall. u-PA-m ediated plasmin generation may contribute to activation of latent MMPs (MMP -3, -9, -12, and -13) which degrade insoluble elastin and fibrillar collage n. Thus, studies with gene-deficient mice have allowed to establish novel inte ractions between the fibrinolytic and MMP systems, which may play a role in biological processes requiring cellular proteolytic activity and/or extrac ellular matrix degradation. (C) 2000 Harcourt Publishers Ltd.