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

Antonietta R. Farina, Lucia Cappabianca, Natalia Di Ianni, Pierdomenico Ruggeri, Marzia Ragone, Stefania Merolle, Alberto Gulino, Andrew R. MacKay

Research output: Contribution to journalArticle

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. Crown

Original languageEnglish
Pages (from-to)2366-2374
Number of pages9
JournalFEBS Letters
Volume586
Issue number16
DOIs
Publication statusPublished - Jul 30 2012

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Keywords

  • Bisphosphonate Alendronate
  • Catalytic-domain
  • Divalent cation chelation
  • Hemopexin-domain
  • Irreversible inhibition
  • MMP-9

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Structural Biology

Cite this

Farina, A. R., Cappabianca, L., Di Ianni, N., Ruggeri, P., Ragone, M., Merolle, S., Gulino, A., & MacKay, A. R. (2012). Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain. FEBS Letters, 586(16), 2366-2374. https://doi.org/10.1016/j.febslet.2012.05.048