July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Secretion of FGF-2 by the Retinal Pigment Epithelium Contributes to Hyaluronan Deposition in Sorsby’s Fundus Dystrophy
Author Affiliations & Notes
  • Alyson Wolk
    Dept. of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, United States
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Jian Hua Qi
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Alecia Cutler
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Mariya Ali
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Brent A. Bell
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Valbona Cali
    Dept. of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States
  • Heidi Stoehr
    Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • Ronald Midura
    Dept. of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States
  • Vincent Hascall
    Dept. of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States
  • Bela Anand-Apte
    Dept. of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, United States
    Dept. of Ophthalmic Research, Cleveland Clinic, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Alyson Wolk, None; Jian Qi, None; Alecia Cutler, None; Mariya Ali, None; Brent Bell, None; Valbona Cali, None; Heidi Stoehr, None; Ronald Midura, None; Vincent Hascall, None; Bela Anand-Apte, None
  • Footnotes
    Support  NIH grants EY027083, T32EY024236, P30EY025585, and a Research to Prevent Blindness Challenge Grant
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3851. doi:
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      Alyson Wolk, Jian Hua Qi, Alecia Cutler, Mariya Ali, Brent A. Bell, Valbona Cali, Heidi Stoehr, Ronald Midura, Vincent Hascall, Bela Anand-Apte; Secretion of FGF-2 by the Retinal Pigment Epithelium Contributes to Hyaluronan Deposition in Sorsby’s Fundus Dystrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3851.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Hyaluronan (HA) is a glycosaminoglycan present in the extracellular matrix. Complex functions of HA have been recently identified and include its role in vascular homeostasis and inflammation. We identified an increase in the deposition of HA in the RPE and choroid of mice carrying the Ser179Cys-Timp3 mutation associated with Sorsby Fundus Dystrophy (SFD). SFD is an autosomal dominant retinal dystrophy that shares a clinical phenotype with age-related macular degeneration (AMD), including the development of sub-RPE deposits and choroidal neovascularization. In this study, we investigate the factors regulating HA deposition by the RPE.

Methods : S179C-TIMP3 and TIMP3-knockout mice are used as models of SFD. ARPE-19 cell lines that stably express S179C-TIMP3 and primary porcine RPE cells were cultured on trans-well filters for at least 3 weeks. HA was evaluated by fluorophore-assisted carbohydrate electrophoresis, ELISA, and immunohistochemistry. Expression of HA synthase and hyaluronidase genes were evaluated by qPCR. HA-associated proteins were evaluated by immunohistochemistry and Western blot.

Results : HA is increased in the serum of AMD patients and in the serum and RPE/choroid of SFD mouse models. However, there were no changes in expression of genes responsible for HA synthesis (HAS1-3) or degradation (HYAL1-2). Rather, increases in HA-associated proteins CD44 and Inter-alpha Trypsin Inhibitor were detected in the RPE of S179C-TIMP3 mice and S179C-TIMP3 ARPE-19 cells. Moreover, the increase in HA seen with S179C-TIMP3 appears to be due to FGF-2. FGF-2 is increased in the conditioned media of S179C-TIMP3 ARPE-19 cells. Primary porcine RPE cells showed increased HA when treated with FGF-2. Treating S179C-TIMP3 ARPE-19 cells with BGJ-398, an inhibitor of FGF Receptors, decreases HA accumulation but has no effect on HA deposition by cells without TIMP3 mutations.

Conclusions : Increased circulating and local levels of HA are markers of pathogenic and inflammatory processes. We hypothesize that increased binding of HA by associated proteins protect HA from degradation, leading to its accumulation. Additionally, FGF-2 appears to mediate pathogenic accumulation of HA but is not responsible for its normal deposition in the matrix. Our results suggest an interesting and novel interplay between FGF and HA that may play a critical role in the pathogenesis of SFD and possibly AMD.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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