FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.

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PROJECT SUMMARY Sorsby fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is characterized by bilateral loss of central vision as a consequence of RPE dystrophy and choroidal neovascularization (CNV). Specific mutations in the TIMP-3 gene involving exon 5 or the intron4-exon5 boundary have been shown to be causative. The age-related macular degeneration (AMD) consortium has identified rare coding variants in the TIMP3 gene when analyzing 16,144 patients and 17,832 controls. The clinical and histopathological similarities between AMD and SFD and the identification of variants in the matrix metalloproteinase pathway in AMD suggest that similar downstream effectors might be in play in both conditions. A better understanding of the pathophysiological mechanisms contributing to the CNV in SFD will provide information that could be potentially useful in AMD. In comparative studies using TIMP-3 deficient mice, S179CTIMP-3 transgenic mice and in vitro culture experiments we have determined that RPE cells expressing mutant TIMP3 undergo epithelial-mesenchymal transformation (EMT) and have altered metabolism. These changes are correlated with increased bFGF and hyaluronan deposition. Based on these results, we hypothesize that under physiological conditions, TIMP3 is required to control and localize matrix degradation in the RPE/choroid which keeps the RPE in an epithelial state and allows for normal metabolic activity. Loss of TIMP3 function in this regard leads to EMT and altered metabolism which could have significant effects on RPE and retinal health.