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X. Zhang, S.K. Chintala; Optic Nerve Ligation Leads to Glial Cell Associated Matrix Metalloproteinase-9 Unduction in the Retina . Invest. Ophthalmol. Vis. Sci. 2003;44(13):5214.
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Purpose: The mechanisms that underlie retinal ganglion cell loss in a number of ischemic blinding diseases are not clearly understood. Employing a mouse model of optic nerve ligation, we previously have shown that ganglion cell loss was associated with matrix metalloproteinase-9 (MMP-9) induction in the retina. The aim of this study was to determine the cellular source of MMP-9, and whether altered levels of tissue inhibitors of metalloproteinases (TIMPs) contribute to increased MMP-9 activity in the retina after optic nerve ligation. Methods: Retinal ganglion cell loss in CD-1 mice was initiated by ligating the optic nerve for 30 min. Various time periods after reperfusion, retinal morphology was assessed by H&E staining. MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in retinal protein extracts was determined by western blot analysis. Tissue localization of MMP-9, vimentin, glial fibrillary acidic protein (GFAP), Mac1, and thy-1 was determined immunofluorescent staining of retinal cross sections. Results: Progressive ganglion cell loss in optic nerve ligated retinas was associated with increased MMP-9 expression. MMP-2, TIMP-1, and 2 proteins were constitutively expressed in the retina and levels of these proteins unchanged after optic nerve ligation. Cells in the inner retina exhibited increased immunoreactivity for glial fibrillary acidic protein (GFAP) whereas similar level of vimentin, a marker for Müller cells, immunoreactivity was found in both control and optic nerve ligated retinas. Antibodies against MMP-9 showed positive immunoreactivity in the inner limiting membrane that was predominantly co-localized with GFAP positive cells. Fewer cells indicated co-localization for both MMP-9 and vimentin. Conclusions: These data indicate that optic nerve ligation leads to MMP-9 induction in the retina by activated glial cells. Our results suggest that induced MMP-9 synthesis by activated glial cells was appropriately localized to trigger ganglion cell death, possibly, due to proteolytic modulation/degradation of the extracellular matrix in the inner limiting membrane.
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