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

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

doi:10.3390/cells9030608

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.

Highlights

Sorsby’s 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 choroidal neovascularization (CNV) [1,2,3,4,5,6]
We have recently reported that retinal pigment epithelium (RPE) cells expressing mutant tissue inhibitor of metalloproteinase-3 (TIMP3) secrete increased amounts of fibroblast growth factor 2 (FGF-2) [28] and that this contributes to increased angiogenesis
To of HA in the RPE as observed in human sections with age-related macular degeneration (AMD), we evaluated accrual of HA in the retinas ascertain that HA binding protein (HABP) binds HA sections were treated with hyaluronidase prior to staining of mice (8 weeks of age) lacking

Summary

Introduction

Sorsby’s 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 choroidal neovascularization (CNV) [1,2,3,4,5,6]. Cells 2020, 9, 608 we have determined that TIMP3 partially inhibits angiogenesis by blocking the binding of vascular endothelial growth factor (VEGF) to VEGF Receptor 2 (VEGFR2). We have demonstrated that the S179C-TIMP3 mutant protein induces angiogenesis via VEGF and fibroblast growth factor 2 (FGF-2) [15,16,17,18,19,20,21]. TIMP3 is produced constitutively by the retinal pigment epithelium (RPE) and choroidal endothelial cells [2,20]. It is a normal component of Bruch’s membrane [22] and binds to sulfated glycosaminoglycans of the extracellular matrix (ECM) [23,24]. Hyaluronan (HA) is a large glycosaminoglycan that is a significant component of peri-cellular and extracellular matrices

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