Binding of latent matrix metalloproteinase 9 to fibrin: activation via a plasmin-dependent pathway

• Published in: Inflammation Vol. 22; no. 3; pp. 287 - 306
• Main Authors: Makowski, G S, Ramsby, M L
• Format: Journal Article
• Language: English
• Published: United States 01-06-1998
• Subjects: Collagenases - blood; Collagenases - chemistry; Collagenases - metabolism; Enzyme Activation - physiology; Fibrin - metabolism; Fibrinolysin - physiology; Gelatinases - blood; Gelatinases - metabolism; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases - blood; Metalloendopeptidases - metabolism; Molecular Weight; Neutrophils - chemistry; Time Factors; Tissue Extracts - metabolism
• ISSN: 0360-3997
• DOI: 10.1023/A:1022300216202

The binding of two matrix metalloproteinases (MMP) to fibrin was evaluated. MMP-2 (72-kDa) and MMP-9 (92-, 130-, and 225-kDa) were selected since both contain a fibronectin-like region and fibronectin binds fibrin. Gelatin zymography indicated selective and dose dependent binding of MMP-9 to fibrin. No MMP-2 binding to fibrin occurred. Densitometry revealed that the 130- and 225-kDa forms demonstrated similar sigmoidal binding profiles whereas 92-kDa uptake was hyperbolic. Fibronectin and TIMP-1 competition studies indicated that the fibronectin and C-terminal MMP-9 domains, respectively, were not involved with fibrin binding. The MMP-9 collagen-like region may be of regulatory significance since type I and II fibrillar and type IV basement membrane collagens demonstrated fibrin binding. During fibrinolysis, latent fibrin-bound MMP-9 was processed to lower molecular weight forms consistent with proteolytic activation. This process was inhibited by epsilon-aminocaproic acid, indicating a plasmin-dependent pathway. The significance of these findings to procoagulant activity and MMP-mediated extracellular matrix destruction during inflammation and tumor invasion and metastasis is discussed.