Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome

Zenkel M, Hoja U, Gießl A, Berner D, Hohberger B, Weller J, König L, Huebner L, Ostermann TA, Gusek-Schneider G, Kruse F, Pasutto F, Schlötzer-Schrehardt U (2022)

Publication Type: Journal article

Publication year: 2022


Book Volume: 23

Journal Issue: 11

DOI: 10.3390/ijms23115977


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-beta 1/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-beta 1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-beta 1 /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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Zenkel, M., Hoja, U., Gießl, A., Berner, D., Hohberger, B., Weller, J.,... Schlötzer-Schrehardt, U. (2022). Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome. International Journal of Molecular Sciences, 23(11). https://doi.org/10.3390/ijms23115977


Zenkel, Matthias, et al. "Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome." International Journal of Molecular Sciences 23.11 (2022).

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