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G. Inana, C. Murat, M. J. McLaren; Transgenic Model of MT1-MMP Over-Expression Exhibits Phenotypic Features of Wet and Dry Forms of Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2009;50(13):773.
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We identified membrane-type matrix metalloproteinase 1 (MT1-MMP) as a candidate gene for AMD by a custom expression profiling strategy called CHANGE based on its 1) over-expression in human AMD eyes, and 2) role in photoreceptor outer segment (OS) phagocytosis by the RPE, a key function and daily burden for the RPE cells which are primarily affected in AMD. We constructed a proof-of-concept transgenic mouse model that conditionally over-expresses MT1-MMP to test the hypothesis that over-expression of MT1-MMP alone can produce a phenotype consistent with AMD. We previously reported a vesicular pattern of RPE degeneration and possible formation of choroidal neovascular membranes (CNV) in this model, consistent with pathologies seen in dry and wet forms of AMD, respectively. The purpose of the present work was to further extend the preliminary findings in the model.
Over-expression of MT1-MMP was induced by doxycycline administration, and the resulting phenotype was studied by histological and immunohistochemical methods after 7-14 days.
Histological analysis confirmed 1) abnormal elongation of OS, 2) leakiness of the RPE layer resulting in subretinal hemorrhage, 3) vesicular degeneration of RPE, 4) sprouting of tubular structures from the choroid, consistent with new blood vessel formation, 5) streaks containing blood components arising from the choroid and traversing the retina, and 6) formation of CNV membranes. Immunostaining of CNV lesions demonstrated expression of MT1-MMP, MMP2, and TIMP2, consistent with active matrix reorganization, and the presence of cells expressing VEGF and endothelial markers CD31 and Flk1.
Over-expression of MT1-MMP in the model led to RPE degeneration, choroidal neovascularization, and CNV membrane formation, with evidence of matrix and vascular activation. These pathological features are associated with dry and wet AMD. The results from the CHANGE analysis, confirmed in the transgenic model, provide evidence for a primary role for MT1-MMP in AMD, and support its consideration as an important new therapeutic target for this disease.
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