101. Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain.
- Author
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Farina AR, Cappabianca L, Di Ianni N, Ruggeri P, Ragone M, Merolle S, Gulino A, and Mackay AR
- Subjects
- Catalysis, Catalytic Domain, Cations, Cell Line, Tumor, Chelating Agents pharmacology, Dose-Response Relationship, Drug, Edetic Acid chemistry, Hemopexin chemistry, Humans, Plasminogen chemistry, Protein Structure, Tertiary, Recombinant Proteins chemistry, Alendronate pharmacology, Fibrinolysin metabolism, Matrix Metalloproteinase 9 metabolism
- Abstract
Irreversible MMP-9 inhibition is considered a significant therapeutic goal in inflammatory, vascular and tumour pathology. We report that divalent cation chelators Alendronate and EDTA not only directly inhibited MMP-9 but also promoted irreversible plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin-degradation sites within the MMP-9 catalytic-domain and producing an inhibitory hemopexin-domain fragment. This effect was also observed using MDA-MB-231 breast cancer cells, which activated exogenous plasminogen to degrade endogenous proMMP-9 in the presence of Alendronate or EDTA. Degradation-mediated inactivation of proMMP-9 occurred in the absence of transient activation, attesting to the incapacity of plasmin to directly activate proMMP-9 and direct MMP-9 inhibition by Alendronate and EDTA. Our study provides a novel rational for therapeutic Alendronate use in MMP-9-dependent pathology characterised by plasminogen activation., (Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2012
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