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Tissue Inhibitor of Metalloproteinase-2 Protection of Matrix Metalloproteinase-2 from Degradation by Plasmin Is Reversed by Divalent Cation Chelator EDTA and the Bisphosphonate Alendronate¹

Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila [A. R. F., A. Ta., A. Te., A. R. M.]; Neuromed Institute, 80077 Pozzilli [A. R. F., A. G., A. R. M.]; and Department of Experimental Medicine and Pathology, University of Rome "La Spaienza," 00161 Rome [A. G.], Italy

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).

¹ This work was supported by grants from the National Research Council, the Italian Ministry for Universities, the Associazione Italiana per la Ricerca sul Cancro, and the Associazione Italiana per la Lotta al Neuroblastoma.

² To whom requests for reprints should be addressed, at Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito II, 67100 L'Aquila, Italy. Phone: (39)-862-433542; Fax: (39)-862-433523; E-mail: farina@aquila.infn.it.

Received 4/ 6/98. Accepted 6/ 1/98.

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