Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome
Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/11/5977 |
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| author | Matthias Zenkel Ursula Hoja Andreas Gießl Daniel Berner Bettina Hohberger Julia M. Weller Loretta König Lisa Hübner Thomas A. Ostermann Gabriele C. Gusek-Schneider Friedrich E. Kruse Francesca Pasutto Ursula Schlötzer-Schrehardt |
| author_facet | Matthias Zenkel Ursula Hoja Andreas Gießl Daniel Berner Bettina Hohberger Julia M. Weller Loretta König Lisa Hübner Thomas A. Ostermann Gabriele C. Gusek-Schneider Friedrich E. Kruse Francesca Pasutto Ursula Schlötzer-Schrehardt |
| author_sort | Matthias Zenkel |
| collection | DOAJ |
| description | Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-β1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-β1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-β1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma. |
| first_indexed | 2024-03-10T01:17:13Z |
| format | Article |
| id | doaj.art-877d8a2ad9db4fb58a4d824b56f41529 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:17:13Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-877d8a2ad9db4fb58a4d824b56f415292023-11-23T14:07:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012311597710.3390/ijms23115977Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation SyndromeMatthias Zenkel0Ursula Hoja1Andreas Gießl2Daniel Berner3Bettina Hohberger4Julia M. Weller5Loretta König6Lisa Hübner7Thomas A. Ostermann8Gabriele C. Gusek-Schneider9Friedrich E. Kruse10Francesca Pasutto11Ursula Schlötzer-Schrehardt12Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyPseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-β1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-β1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-β1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma.https://www.mdpi.com/1422-0067/23/11/5977pseudoexfoliation syndromepseudoexfoliation glaucomaretinolretinoic acidextracellular matrixfibrosis |
| spellingShingle | Matthias Zenkel Ursula Hoja Andreas Gießl Daniel Berner Bettina Hohberger Julia M. Weller Loretta König Lisa Hübner Thomas A. Ostermann Gabriele C. Gusek-Schneider Friedrich E. Kruse Francesca Pasutto Ursula Schlötzer-Schrehardt Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome International Journal of Molecular Sciences pseudoexfoliation syndrome pseudoexfoliation glaucoma retinol retinoic acid extracellular matrix fibrosis |
| title | Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome |
| title_full | Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome |
| title_fullStr | Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome |
| title_full_unstemmed | Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome |
| title_short | Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome |
| title_sort | dysregulated retinoic acid signaling in the pathogenesis of pseudoexfoliation syndrome |
| topic | pseudoexfoliation syndrome pseudoexfoliation glaucoma retinol retinoic acid extracellular matrix fibrosis |
| url | https://www.mdpi.com/1422-0067/23/11/5977 |
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