Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain.
FEBS Lett
; 586(16): 2366-74, 2012 Jul 30.
Article
em En
| MEDLINE
| ID: mdl-22677171
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fibrinolisina
/
Alendronato
/
Metaloproteinase 9 da Matriz
Limite:
Humans
Idioma:
En
Revista:
FEBS Lett
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Itália