Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome

Medientyp: E-Artikel

Titel: Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome

Beteiligte: Zenkel, Matthias; Hoja, Ursula; Gießl, Andreas; Berner, Daniel; Hohberger, Bettina; Weller, Julia M.; König, Loretta; Hübner, Lisa; Ostermann, Thomas A.; Gusek-Schneider, Gabriele C.; Kruse, Friedrich E.; Pasutto, Francesca; Schlötzer-Schrehardt, Ursula

Erschienen: MDPI AG, 2022

Sprache: Englisch

DOI: 10.3390/ijms23115977

ISSN: 1422-0067

Schlagwörter: Inorganic Chemistry ; Organic Chemistry ; Physical and Theoretical Chemistry ; Computer Science Applications ; Spectroscopy ; Molecular Biology ; General Medicine ; Catalysis

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Beschreibung: 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.

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