Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain

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• 作者：Antonietta R. Farina ; Lucia Cappabianca ; Natalia Di Ianni ; Pierdomenico Ruggeri ; Marzia Ragone ; Stefania Merolle ; Alberto Gulino ; Andrew R. Mackay
• 关键词：MMP-9 ; matrix metalloproteinase-9 ; TIMP ; tissue inhibitor of metalloproteinases ; APMA ; aminophenylmercuric acetate ; EDTA ; ethylenediaminetetraacetic acid
• 刊名：FEBS Letters
• 出版年：2012
• 出版时间：30 July, 2012
• 年：2012
• 卷：586
• 期：16
• 页码：2366-2374
• 全文大小：793 K

文摘

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.