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Q Ebrahem, JH Qi, B Anand-Apte; Induction of an Angiogenic Phenotype in Human Retinal Pigment Epithelial Cells Expressing Sorsby's Fundus Dystrophy Mutation . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2803.
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Purpose: Sorsby's fundus dystrophy (SFD) is a dominantly inherited condition characterized by the development of choroidal neovascular membranes, subretinal hemorrhages and changes consistent with disciform degeneration. Choroidal neovascularization is an important pathological feature of eye diseases such as age-related macular degeneration. A precise spatial and temporal regulation of extracellular proteolysis is required for neovascularization. Tissue Inhibitor of Metalloproteinases-3 (TIMP-3), a regulator of matrix metalloproteinases (MMPs) is deposited by retinal pigment epithelial (RPE) cells into Bruch's membrane where it is a component of the extracellular matrix. Mutations in the TIMP-3 gene, all of which introduce an extra cysteine residue into exon 5, have been linked to SFD. In this study we set out to elucidate the mechanism by which TIMP-3 mutations induce the disease phenotype. Methods: We have expressed a SFD mutant TIMP-3 (S156C) in which the serine 156 was changed to a cysteine, in the human RPE cell line, ARPE-19. The ability of the conditioned medium to induce angiogenesis was tested using in vitro (endothelial cell migration and proliferation) and in vivo (chick chorio-allantoic membrane) angiogenesis assays. Results: The conditioned medium from RPE cells expressing SFD mutant TIMP-3 induced endothelial cell migration. The conditioned medium from these cells also induced angiogenesis in the chick chorio-allantoic membrane assay, which could be reversed by recombinant wild type TIMP-3. Conclusion: Our data indicate that the choroidal neovascularization in SFD may be a result of haplo-insuffficiency of TIMP-3, which leads to increased MMP activity and the stimulation of angiogenesis.
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