Tissue inhibitor of metalloproteinase-2 protection of matrix metalloproteinase-2 from degradation by plasmin is reversed by divalent cation chelator EDTA and the bisphosphonate alendronate

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 14; pp. 2957 - 2960
• Main Authors: FARINA, A. R, TACCONELLI, A, TETI, A, GULINO, A, MACKAY, A. R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-1998
• Subjects: Alendronate - pharmacology; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cations; Chelating Agents - pharmacology; Diphosphonates - pharmacology; Edetic Acid - pharmacology; Fibrinolysin - antagonists & inhibitors; Fibrinolysin - metabolism; Fundamental and applied biological sciences. Psychology; Gelatinases - drug effects; Gelatinases - metabolism; Humans; Matrix Metalloproteinase 2; Metalloendopeptidases - drug effects; Metalloendopeptidases - metabolism; Metalloproteins; Other metalloproteins; Protease Inhibitors - pharmacology; Proteins; Tissue Inhibitor of Metalloproteinase-2 - pharmacology; Tumor Cells, Cultured - drug effects; Human; Serine endopeptidases; Enzyme; Enzyme inhibitor; Diphosphonic acid derivatives; Metalloendopeptidases; EDTA; Bisphosphonates; In vitro; Plasmin; Peptidases; Alendronic acid; Enzymatic activity; Proteolysis; Hydrolases; Cell free system
• ISSN: 0008-5472; 1538-7445

The degradation of tissue inhibitor of metalloproteinase (TIMP)-free matrix metalloproteinase (MMP)-2 to proteolytically inactive fragments by plasmin was inhibited in equimolar mixtures of purified TIMP-2 and TIMP-free MMP-2 and was not observed in purified MMP-2-TIMP-2 complexes. Divalent cation chelators EDTA and sodium Alendronate did not inhibit plasmin degradation of TIMP-free MMP-2 but reversed the ability of TIMP-2 to protect MMP-2 from degradation by plasmin. Our data confirm a role for plasmin in the clearance of TIMP-free MMP-2, identify a pivotal role for TIMP-2 in regulating MMP-2 longevity in plasmin-containing environments, and highlight a novel therapeutic use for chelators of divalent cations, including the bisphosphonate Alendronate, in the reversal of TIMP-2 protection of MMP-2 from degradation by plasmin. We propose that these observations are relevant to pathologies that are dependent upon plasmin and MMP-2 activity (e.g., tumor invasion and metastasis).