CCN2/CTGF tip the balance of growth factors towards TGF-beta 2 in primary open-angle glaucoma

TGF-beta 2 is the predominant TGF-beta isoform within the eye. One function of TGF-beta 2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-beta 2 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-beta 2 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-beta 2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-beta 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-beta 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 (beta B1-CTGF1) and a high CCN2/CTGF (beta B1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-beta effects via different pathways. We observed developmental malformations in the ciliary body in beta B1-CTGF6 caused by an inhibition of the BMP signaling pathway. In beta B1-CTGF1, we detected a dysregulation of the BMP and TGF-beta signaling pathways, with reduced BMP activity and increased TGF-beta signaling. A direct CCN2/CTGF effect on BMP and TGF-beta signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-beta 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-beta signaling pathways, which is shifted in primary open-angle glaucoma.