TISSUE INHIBITOR OF METALLOPROTEINASE-2 PROTECTION OF MATRIX METALLOPROTEINASE-2 FROM DEGRADATION BY PLASMIN IS REVERSED BY DIVALENT-CATIONCHELATOR EDTA AND THE BISPHOSPHONATE ALENDRONATE

The degradation of tissue inhibitor of metalloproteinase (TIMP)-free m atrix 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 complexe s. Divalent cation chelators EDTA and sodium Alendronate did not inhib it 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 piv otal role for TIMP-2 in regulating MMP-2 longevity in plasmin-containi ng environments, and highlight a novel therapeutic use for chelators o f divalent cations, including the bisphosphonate.Alendronate, in the r eversal of TIMP-2 protection of MMP-2 from degradation by plasmin. We propose that these observations are relevant to pathologies that are d ependent upon plasmin and MMP-2 activity (e.g., tumor invasion and met astasis).