Expression and Impact of Fibronectin, Tenascin-C, Osteopontin, and Type XIV Collagen in Fuchs Endothelial Corneal Dystrophy

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Abstract

Purpose

Fuchs endothelial corneal dystrophy (FECD) is characterized by Descemet's membrane (DM) abnormalities, namely an increased thickness and a progressive appearance of guttae and fibrillar membranes. The goal of this study was to identify abnormal extracellular matrix (ECM) proteins expressed in FECD DMs and to evaluate their impact on cell adhesion and migration.

Methods

Gene expression profiles from in vitro (GSE112039) and ex vivo (GSE74123) healthy and FECD corneal endothelial cells were analyzed to identify deregulated matrisome genes. Healthy and end-stage FECD DMs were fixed and analyzed for guttae size and height. Immunostaining of fibronectin, tenascin-C, osteopontin, and type XIV collagen was performed on ex vivo specimens, as well as on tissue-engineered corneal endothelium reconstructed using healthy and FECD cells. An analysis of ECM protein expression according to guttae and fibrillar membrane was performed using immunofluorescent staining and phase contrast microscopy. Finally, cell adhesion was evaluated on fibronectin, tenascin-C, and osteopontin, and cell migration was studied on fibronectin and tenascin-C.

Results

SPP1 (osteopontin), FN1 (fibronectin), and TNC (tenascin-C) genes were upregulated in FECD ex vivo cells, and SSP1 was upregulated in both in vitro and ex vivo FECD conditions. Osteopontin, fibronectin, tenascin-C, and type XIV collagen were expressed in FECD specimens, with differences in their location. Corneal endothelial cell adhesion was not significantly affected by fibronectin or tenascin-C but was decreased by osteopontin. The combination of fibronectin and tenascin-C significantly increased cell migration.

Conclusions

This study highlights new abnormal ECM components in FECD, suggests a certain chronology in their deposition, and demonstrates their impact on cell behavior.

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Most cited references 61

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TGF-beta signaling and the fibrotic response.

Andrew Leask, David J. Abraham (2004)

The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma).

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Corneal blindness: a global perspective.

Sudha Srinivasan, Kelvin J. Whitcher, Ravi Upadhyay … (2000)

Diseases affecting the cornea are a major cause of blindness worldwide, second only to cataract in overall importance. The epidemiology of corneal blindness is complicated and encompasses a wide variety of infectious and inflammatory eye diseses that cause corneal scarring, which ultimately leads to functional blindness. In addition, the prevalence of corneal disease varies from country to country and even from one population to another. While cataract is responsible for nearly 20 million of the 45 million blind people in the world, the next major cause is trachoma which blinds 4.9 million individuals, mainly as a result of corneal scarring and vascularization. Ocular trauma and corneal ulceration are significant causes of corneal blindness that are often underreported but may be responsible for 1.5-2.0 million new cases of monocular blindness every year. Causes of childhood blindness (about 1.5 million worldwide with 5 million visually disabled) include xerophthalmia (350,000 cases annually), ophthalmia neonatorum, and less frequently seen ocular diseases such as herpes simplex virus infections and vernal keratoconjunctivitis. Even though the control of onchocerciasis and leprosy are public health success stories, these diseases are still significant causes of blindness--affecting a quarter of a million individuals each. Traditional eye medicines have also been implicated as a major risk factor in the current epidemic of corneal ulceration in developing countries. Because of the difficulty of treating corneal blindness once it has occurred, public health prevention programmes are the most cost-effective means of decreasing the global burden of corneal blindness.

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Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy.

Ula V Jurkunas, Maya S Bitar, Toshinari Funaki … (2010)

Fuchs endothelial corneal dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial (CE) cell apoptosis. Corneal transplantation is the only measure currently available to restore vision in these patients. Despite the identification of some genetic factors, the pathophysiology of FECD remains unclear. In this study, we observed a decrease in the antioxidant response element-driven antioxidants in FECD corneal endothelium. We further demonstrated that nuclear factor erythroid 2-related factor 2, a transcription factor known to bind the antioxidant response element and activate antioxidant defense, is down-regulated in FECD endothelium. Importantly, we detected significantly higher levels of oxidative DNA damage and apoptosis in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy (iatrogenic CE cell loss) specimens. A marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, colocalized to mitochondria, indicating that the mitochondrial genome is the specific target of oxidative stress in FECD. Oxidative DNA damage was not detected in pseudophakic bullous keratopathy corneas, whereas it colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in FECD samples. Ex vivo, oxidative stress caused characteristic morphological changes and apoptosis of CE, suggestive of findings that characterize FECD in vivo. Together, these data suggest that suboptimal nuclear factor erythroid 2-related factor 2-regulated defenses may account for oxidant-antioxidant imbalance in FECD, which in turn leads to oxidative DNA damage and apoptosis. This study provides evidence that oxidative stress plays a key role in FECD pathogenesis.

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Author and article information

Journal

Journal ID (nlm-ta): Invest Ophthalmol Vis Sci

Journal ID (iso-abbrev): Invest Ophthalmol Vis Sci

Journal ID (publisher-id): IOVS

Title: Investigative Ophthalmology & Visual Science

Publisher: The Association for Research in Vision and Ophthalmology

ISSN (Print): 0146-0404

ISSN (Electronic): 1552-5783

Publication date (Electronic): 24 April 2024

Publication date Collection: April 2024

Volume: 65

Issue: 4

Electronic Location Identifier: 38

Affiliations

[1 ]Centre de recherche du CHU de Québec–Université Laval, axe médecine régénératrice, Québec, Québec, Canada

[2 ]Département d'ophtalmologie et d'ORL–CCF, Faculté de médecine, Université Laval, Québec, Québec, Canada

[3 ]Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Québec, Québec, Canada

[4 ]Centre de recherche de l'hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada

Author notes

[* ]Correspondence: Stéphanie Proulx, Centre de recherche du CHU de Québec–Université Laval, Hôpital du Saint-Sacrement, 1050 chemin Ste-Foy, Québec, QC G1S 4L8, Canada; stephanie.proulx@ 123456fmed.ulaval.ca .

Article

Publisher ID: IOVS-23-38610

DOI: 10.1167/iovs.65.4.38

PMC ID: 11044831

PubMed ID: 38656280

SO-VID: e775304a-0d1a-415c-8844-d77520fe6c89

License:

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

History

Date accepted : 02 April 2024

Date received : 23 September 2023

Page count

Pages: 12

Expression and Impact of Fibronectin, Tenascin-C, Osteopontin, and Type XIV Collagen in Fuchs Endothelial Corneal Dystrophy

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Abstract

Purpose

Methods

Results

Conclusions

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Most cited references 61

TGF-beta signaling and the fibrotic response.

Corneal blindness: a global perspective.

Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy.

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