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

10 Citations (Scopus)

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

Fingerprint

Alendronate
Fibrinolysin
Matrix Metalloproteinases
Catalytic Domain
Degradation
Edetic Acid
Plasminogen
Pathology
Chemical activation
Hemopexin
Divalent Cations
Therapeutic Uses
Chelating Agents
Crowns
Blood Vessels
Tumors
Cells
Breast Neoplasms
Neoplasms

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., ... 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

Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain. / Farina, Antonietta R.; Cappabianca, Lucia; Di Ianni, Natalia; Ruggeri, Pierdomenico; Ragone, Marzia; Merolle, Stefania; Gulino, Alberto; MacKay, Andrew R.

In: FEBS Letters, Vol. 586, No. 16, 30.07.2012, p. 2366-2374.

Research output: Contribution to journalArticle

Farina, AR, Cappabianca, L, Di Ianni, N, Ruggeri, P, Ragone, M, Merolle, S, Gulino, A & MacKay, AR 2012, 'Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain', FEBS Letters, vol. 586, no. 16, pp. 2366-2374. https://doi.org/10.1016/j.febslet.2012.05.048
Farina, Antonietta R. ; Cappabianca, Lucia ; Di Ianni, Natalia ; Ruggeri, Pierdomenico ; Ragone, Marzia ; Merolle, Stefania ; Gulino, Alberto ; MacKay, Andrew R. / Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain. In: FEBS Letters. 2012 ; Vol. 586, No. 16. pp. 2366-2374.
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