Purchase this article with an account.
Lies De Groef, Manuel Salinas-Navarro, Eline Dekeyster, Kim Lemmens, Djoere Gaublomme, Inge Van Hove, Lieve Moons; Neuroprotection from excitotoxic RGC death: is there a role for MMPs?. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4943.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Multiple studies in glaucoma patients and animal models, have reported differential expression and activity of matrix metalloproteinase (MMPs). These data have led to the hypothesis that MMPs are involved in glaucoma pathogenesis. However, their in vivo functions remain poorly understood. Here, we investigate the contribution of MMPs to retinal ganglion cell (RGC) death in the excitotoxic mouse retina and reveal that MMP-2, -3 and -9 deficient mice are -at least partially- protected from excitotoxic RGC death.
Excitotoxic RGC death was induced via intravitreal injection of 20 mM NMDA, both in wild type and MMP-2, -3 or -9 deficient mice (N>5). Expression of MMPs was examined via immunohistochemistry and Western blot. RGC survival was assessed by quantifying the number of survival RGCs after Brn3a immunostaining on whole mounted retinas using a custom-made automated routine.
MMP-9 is expressed by RGCs and microglia and also shows strong immunoreactivity in the inner limiting membrane. MMP-2 and -3, on the other hand, have a macroglial origin and are expressed throughout all layers of the mouse retina. At 24 hours post NMDA injection (24hpi), a strong upregulation of MMP-3 and -9 expression is seen, whereas MMP-2 levels only increase modestly. MMP-9 deficiency protects retinas from NMDA-induced RGC death. Also in MMP-2-/- and MMP-3-/- mice, RGC death is attenuated. Whereas only 17.0±0.05% of the RGCs survive in wild type mice at 24hpi, RGC survival is increased to 34.01±0.01% and 33.99±0.05% in, respectively, MMP-2-/- and MMP-3-/- animals. We are currently analyzing time-dependent cellular changes within the excitotoxic retina and investigating possible underlying mechanisms.
MMP-2, -3 and -9 deficiency reduces RGC death in an excitotoxic mouse glaucoma model. For MMP-9, this is in accordance to what has been shown in an optic nerve ligation glaucoma model and most likely related to anoikis of RGCs. On the other hand, for MMP-2 and -3, this neuroprotective effect might be related to modulation of the glial reactivity accompanying RGC degeneration, as suggested by their glial expression pattern.
This PDF is available to Subscribers Only