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.