Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domain.
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.
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy.
Antonietta R
AR
Farina
Lucia
L
Cappabianca
Natalia
N
Di Ianni
Pierdomenico
P
Ruggeri
Marzia
M
Ragone
Stefania
S
Merolle
Alberto
A
Gulino
Andrew R
AR
Mackay
D019386:Alendronate / Q000494:pharmacology*; D002384:Catalysis; D020134:Catalytic Domain; D002412:Cations; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000737:chemistry; D005341:Fibrinolysin / Q000378:metabolism*; D006466:Hemopexin / Q000737:chemistry; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010958:Plasminogen / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
D002412:Cations; D002614:Chelating Agents; D011994:Recombinant Proteins; D010958:Plasminogen; D006466:Hemopexin; D004492:Edetic Acid; D005341:Fibrinolysin; D020780:Matrix Metalloproteinase 9; D019386:Alendronate