Plasminogen/plasmin system function in mice deficient in stromelysin-1 (MMP-3) or in tissue inhibitor of metalloproteinases type-1 (TIMP-1)

Abstract

Specific interactions between the plasminogen/plasmin (fibrinolytic) and matrix metalloproteinase (MMP) systems suggest that both systems may cooperate in extracellular matrix degradation. Therefore, the plasminogen/plasmin system function was evaluated in mice with stromelysin-1 (MMP-3) or tissue inhibitor of MMP type-1 (TIMP-1) gene inactivation. Urinary urokinase-type plasminogen activator (u-PA) antigen (120–190 ng/ml) and activity (13–18 IU/ml) levels were similar in both wild-type and gene-deficient mice. Vascular plasminogen activator activity, measured in aorta extracts, was similar for both tissue-type plasminogen activator (t-PA)-mediated activity (8–14 arbitrary units (AU) per mg protein) and for u-PA-mediated activity (25–34 AU per mg protein). The spontaneous thrombolytic potential (lysis of a 125 I-fibrin labelled pulmonary embolus) was comparable in wild-type (MMP-3 +/+ ) and MMP-3 −/− mice (36 ± 6% versus 49 ± 5% after 8 h; P = 0.13), and in wild-type (TIMP-1 +/+ ) and TIMP-1 −/− mice (48 ± 4% versus 48 ± 2% after 8 h). Organ sections did not reveal significant fibrin deposition in the liver of any of the genotypes. Furthermore, in vivo thioglycollate-stimulated macrophages of all 4 genotypes expressed comparable u-PA-mediated plasminogen activating potential and 125 I-fibrin matrix degrading potential. Thus, these data suggest that MMP-3 and TIMP-1 do not play a major role in the generation of fibrinolytic activity mediated via the plasminogen/plasmin system.