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CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma

TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network ca...

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Autores principales: Dillinger, Andrea E., Kuespert, Sabrina, Seleem, Amin A., Neuendorf, Jakob, Schneider, Magdalena, Fuchshofer, Rudolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10210157/
https://www.ncbi.nlm.nih.gov/pubmed/37251082
http://dx.doi.org/10.3389/fmolb.2023.1045411
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author Dillinger, Andrea E.
Kuespert, Sabrina
Seleem, Amin A.
Neuendorf, Jakob
Schneider, Magdalena
Fuchshofer, Rudolf
author_facet Dillinger, Andrea E.
Kuespert, Sabrina
Seleem, Amin A.
Neuendorf, Jakob
Schneider, Magdalena
Fuchshofer, Rudolf
author_sort Dillinger, Andrea E.
collection PubMed
description TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network can result in different eye diseases. In Primary Open-Angle Glaucoma (POAG), one of the leading causes of irreversible blindness worldwide, TGF-β2 is significantly elevated in the aqueous humor and antagonistic molecules like BMPs are reduced. The changes provoke an altering of the quantity and quality of the extracellular matrix and the actin cytoskeleton in the outflow tissues, leading to an increased outflow resistance and thereby to an increased intraocular pressure (IOP), the major risk factor for primary open-angle glaucoma. The pathologic effect of TGF-β2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-β and BMP signaling by direct binding. The eye specific overexpression of CCN2/CTGF caused an increase in IOP and led to a loss of axons, the hallmark of primary open-angle glaucoma. CCN2/CTGF appears to play a critical role in the homeostatic balance of the eye, so we investigated if CCN2/CTGF can modulate BMP and TGF-β signaling pathways in the outflow tissues. To this end, we analyzed the direct effect of CCN2/CTGF on both signaling pathways in two transgenic mouse models with a moderate (βB1-CTGF1) and a high CCN2/CTGF (βB1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-β effects via different pathways. We observed developmental malformations in the ciliary body in βB1-CTGF6 caused by an inhibition of the BMP signaling pathway. In βB1-CTGF1, we detected a dysregulation of the BMP and TGF-β signaling pathways, with reduced BMP activity and increased TGF-β signaling. A direct CCN2/CTGF effect on BMP and TGF-β signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-β via the RhoA/ROCK and ERK signaling in immortalized HTM cells. We conclude that CCN2/CTGF functions as a modulator of the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in primary open-angle glaucoma.
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spelling pubmed-102101572023-05-26 CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma Dillinger, Andrea E. Kuespert, Sabrina Seleem, Amin A. Neuendorf, Jakob Schneider, Magdalena Fuchshofer, Rudolf Front Mol Biosci Molecular Biosciences TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network can result in different eye diseases. In Primary Open-Angle Glaucoma (POAG), one of the leading causes of irreversible blindness worldwide, TGF-β2 is significantly elevated in the aqueous humor and antagonistic molecules like BMPs are reduced. The changes provoke an altering of the quantity and quality of the extracellular matrix and the actin cytoskeleton in the outflow tissues, leading to an increased outflow resistance and thereby to an increased intraocular pressure (IOP), the major risk factor for primary open-angle glaucoma. The pathologic effect of TGF-β2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-β and BMP signaling by direct binding. The eye specific overexpression of CCN2/CTGF caused an increase in IOP and led to a loss of axons, the hallmark of primary open-angle glaucoma. CCN2/CTGF appears to play a critical role in the homeostatic balance of the eye, so we investigated if CCN2/CTGF can modulate BMP and TGF-β signaling pathways in the outflow tissues. To this end, we analyzed the direct effect of CCN2/CTGF on both signaling pathways in two transgenic mouse models with a moderate (βB1-CTGF1) and a high CCN2/CTGF (βB1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-β effects via different pathways. We observed developmental malformations in the ciliary body in βB1-CTGF6 caused by an inhibition of the BMP signaling pathway. In βB1-CTGF1, we detected a dysregulation of the BMP and TGF-β signaling pathways, with reduced BMP activity and increased TGF-β signaling. A direct CCN2/CTGF effect on BMP and TGF-β signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-β via the RhoA/ROCK and ERK signaling in immortalized HTM cells. We conclude that CCN2/CTGF functions as a modulator of the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in primary open-angle glaucoma. Frontiers Media S.A. 2023-05-11 /pmc/articles/PMC10210157/ /pubmed/37251082 http://dx.doi.org/10.3389/fmolb.2023.1045411 Text en Copyright © 2023 Dillinger, Kuespert, Seleem, Neuendorf, Schneider and Fuchshofer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Dillinger, Andrea E.
Kuespert, Sabrina
Seleem, Amin A.
Neuendorf, Jakob
Schneider, Magdalena
Fuchshofer, Rudolf
CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title_full CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title_fullStr CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title_full_unstemmed CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title_short CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma
title_sort ccn2/ctgf tip the balance of growth factors towards tgf-β2 in primary open-angle glaucoma
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10210157/
https://www.ncbi.nlm.nih.gov/pubmed/37251082
http://dx.doi.org/10.3389/fmolb.2023.1045411
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