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.
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).
Farina
A R
AR
Department of Experimental Medicine, University of L'Aquila, Italy. farina@aquila.infn.it
Tacconelli
A
A
Teti
A
A
Gulino
A
A
Mackay
A R
AR
D019386:Alendronate / Q000494:pharmacology; D002412:Cations; D002614:Chelating Agents / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018093:Gelatinases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000187:drug effects* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002412:Cations; D002614:Chelating Agents; D004164:Diphosphonates; D011480:Protease Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D004492:Edetic Acid; D005341:Fibrinolysin; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D019386:Alendronate