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Lies De Groef, Roosmarijn Vandenbroucke, Manuel Salinas-Navarro, Inge Van Hove, Claude Libert, Lieve K M Moons; Low TNF levels and increased glutamine synthetase expression in MMP-2 deficient mice result in decreased sensitivity to NMDA-induced retinal ganglion cell death. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3668.
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© ARVO (1962-2015); The Authors (2016-present)
Matrix metalloproteinases (MMPs) are essential to the development and maintenance of a healthy CNS, by cleaving extracellular matrix components, signaling molecules, cell surface receptors, etc. However, various studies in animal models and human patients also suggest their involvement in glaucoma. In this study, we sought to determine the role of MMP-2 during glaucoma pathogenesis.
MMP-2-/- (KO) and wild type (WT) mice received an intravitreal injection of NMDA or underwent optic nerve crush (ONC) to induce retinal ganglion cell death (RGC), which was quantified resp. after 24 hours or 4 days, by means of a Brn3a immunohistochemistry (IHC) on whole mount retinas. The spatiotemporal expression pattern of MMP-2 was quantified by means of gelatin zymography and IHC. Glutamine synthetase (GS) levels were assessed via Western blot and (pro-)TNF was measured using bioplex and a bio-assay.
Double IHC with vimentin and GS revealed that MMP-2 expression localizes to the Müller glia. In the excitotoxic retina, MMP-2 activity increases at 6 hours post injury (hpi), reaches a maximum at 18hpi and then returns to baseline levels by 24hpi. Interestingly, KO mice are partially protected from excitotoxic RGC death (KO 77±2% vs. WT 58±8% RGC survival), while this is not the case after ONC (KO 63±9% vs. WT 73±10% survival). This selective neuroprotective effect might be related to the higher baseline GS expression in KO as compared to WT mice (182±32% vs. WT), which could indicate a more efficient glutamate metabolism. On the other hand, the increase in TNF levels after NMDA administration is less in KO mice (89±3% vs. WT), which could also contribute to the increased RGC survival seen in the KO mice.
MMP-2 is known to act as a pro-TNF converting enzyme, resulting in less TNF activation in the retina of KO mice subjected to a local excitotoxic insult. In addition, KO mice display increased resistance to NMDA-induced RGC death, which might be related to a dual effect of reduced TNF levels. On the one hand, TNF acts as a promotor of apoptosis and as such reduced TNF could directly result in decreased RGC death. On the other hand, TNF also acts as a suppressor of GS expression, explaining the higher GS levels seen in KO mice and potentially resulting in an enhanced capacity of MMP-2 to cope with excitotoxic stress.
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