Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism

Choroidal neovascularization (CNV) leads to loss of vision in patients with Sorsby Fundus Dystrophy (SFD), an inherited, macular degenerative disorder, caused by mutations in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene. SFD closely resembles age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly population of the Western hemisphere. Variants in TIMP3 gene have recently been identified in patients with AMD. A majority of patients with AMD also lose vision as a consequence of choroidal neovascularization (CNV). Thus, understanding the molecular mechanisms that contribute to CNV as a consequence of TIMP-3 mutations will provide insight into the pathophysiology in SFD and likely the neovascular component of the more commonly seen AMD. While the role of VEGF in CNV has been studied extensively, it is becoming increasingly clear that other factors likely play a significant role. The objective of this study was to test the hypothesis that basic Fibroblast Growth Factor (bFGF) regulates SFD-related CNV. In this study we demonstrate that mice expressing mutant TIMP3 (Timp3(S179C/S179C)) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury. S179C mutant-TIMP3 in retinal pigment epithelial (RPE) cells showed increased secretion of bFGF and conditioned medium from these cells induced increased angiogenesis in endothelial cells. These studies suggest that S179C-TIMP3 may promote angiogenesis and CNV via a FGFR-1-dependent pathway by increasing bFGF release and activity.