Farina A R, Tacconelli A, Teti A, Gulino A, Mackay A R
Department of Experimental Medicine, University of L'Aquila, Italy.
Cancer Res. 1998 Jul 15;58(14):2957-60.
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).
在纯化的组织金属蛋白酶抑制剂-2（TIMP-2）与无TIMP的基质金属蛋白酶-2（MMP-2）的等摩尔混合物中，纤溶酶将无TIMP的MMP-2降解为蛋白水解无活性片段的过程受到抑制，而在纯化的MMP-2-TIMP-2复合物中未观察到这种降解。二价阳离子螯合剂乙二胺四乙酸（EDTA）和阿仑膦酸钠不抑制无TIMP的MMP-2的纤溶酶降解，但可逆转TIMP-2保护MMP-2免受纤溶酶降解的能力。我们的数据证实了纤溶酶在清除无TIMP的MMP-2中的作用，确定了TIMP-2在含纤溶酶环境中调节MMP-2寿命方面的关键作用，并突出了二价阳离子螯合剂（包括双膦酸盐阿仑膦酸钠）在逆转TIMP-2对MMP-2的保护使其免受纤溶酶降解方面的新治疗用途。我们认为这些观察结果与依赖纤溶酶和MMP-2活性的病理情况（如肿瘤侵袭和转移）相关。
