Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII.
The effects of plasma proteins on controlling the activity of matrix metalloproteinases (MMPs, matrixins) have been the focus of numerous studies, although only a few have examined the influence of matrixins on plasma proteins. Recently, it has been shown that MMPs may play a role in the degradation of fibrin. We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. Our data demonstrate that the catalytic domains of MMP-8, MMP-12, MMP-13, and MMP-14 can proteolytically process fibrinogen and, with the exception of MMP-8, also inactivate Factor XII (Hageman factor). We have identified the amino termini of the major protein fragments. Cleavage of fibrinogen occurred in all chains and resulted in significantly impaired clotting. Moreover, rapid proteolytic inactivation of Factor XII (Hageman factor) by MMP-12, MMP-13, and MMP-14 was noted. These results support the hypothesis of an impaired thrombolytic potential of MMP-degraded Factor XII in vivo. MMP-induced degradation of fibrinogen supports a plasmin-independent fibrinolysis mechanism. Consequently, degradation of these proteins may be important in inflammation, atherosclerosis, and angiogenesis, all of which are known to be influenced by MMP activity.
Hiller
O
O
Department of Biochemistry, Faculty of Chemistry, University of Bielefeld, 33615 Bielefeld, Germany.
Lichte
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Oberpichler
A
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Kocourek
A
A
Tschesche
H
H
D000595:Amino Acid Sequence; D000925:Anticoagulants; D001777:Blood Coagulation; D017364:Collagenases / Q000378:metabolism*; D005174:Factor XII / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
D000925:Anticoagulants; D010446:Peptide Fragments; D005174:Factor XII; D005340:Fibrinogen; D013917:Thrombin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020784:Matrix Metalloproteinase 8; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12