{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:41:31Z","timestamp":1790710891008,"version":"4.1.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FU738\/6-1 FU738\/4-3"],"award-info":[{"award-number":["FU738\/6-1 FU738\/4-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>TGF-\u03b22 is the predominant TGF-\u03b2 isoform within the eye. One function of TGF-\u03b22 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-\u03b22 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-\u03b22 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-\u03b22 in primary open-angle glaucoma is mainly meditated by CCN2\/CTGF. CCN2\/CTGF can modulate TGF-\u03b2 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-\u03b2 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 (\u03b2B1-CTGF1) and a high CCN2\/CTGF (\u03b2B1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2\/CTGF mediates TGF-\u03b2 effects via different pathways. We observed developmental malformations in the ciliary body in \u03b2B1-CTGF6 caused by an inhibition of the BMP signaling pathway. In \u03b2B1-CTGF1, we detected a dysregulation of the BMP and TGF-\u03b2 signaling pathways, with reduced BMP activity and increased TGF-\u03b2 signaling. A direct CCN2\/CTGF effect on BMP and TGF-\u03b2 signaling was shown in immortalized HTM cells. Finally, CCN2\/CTGF mediated its effects on TGF-\u03b2 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-\u03b2 signaling pathways, which is shifted in primary open-angle glaucoma.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1045411","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T11:22:01Z","timestamp":1683804121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["CCN2\/CTGF tip the balance of growth factors towards TGF-\u03b22 in primary open-angle glaucoma"],"prefix":"10.3389","volume":"10","author":[{"given":"Andrea E.","family":"Dillinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Kuespert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin A.","family":"Seleem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Neuendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Fuchshofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/ncb826","article-title":"Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta","volume":"4","author":"Abreu","year":"2002","journal-title":"Nat. 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