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  • Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy.

Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy.

Cells (2020-03-08)
Alyson Wolk, Dilara Hatipoglu, Alecia Cutler, Mariya Ali, Lestella Bell, Jian Hua Qi, Rupesh Singh, Julia Batoki, Laura Karle, Vera L Bonilha, Oliver Wessely, Heidi Stoehr, Vincent Hascall, Bela Anand-Apte
ABSTRACT

Sorsby's fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Heparin sodium salt from porcine intestinal mucosa, Grade I-A, ≥180 USP units/mg, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Hyaluronidase from Streptomyces hyalurolyticus
Sigma-Aldrich
Hyaluronic Acid Binding Protein, Bovine Nasal Cartilage, Biotinylated