The role of TGF-β in the pathogenesis of primary open-angle glaucoma

Abstract

Transforming growth factor-β2 (TGF-β2) is found in increasing amounts in aqueous humor and reactive optic nerve astrocytes of patients with primary open-angle glaucoma (POAG), a major cause of blindness worldwide. The available data strongly indicate that TGF-β2 is a key player contributing to the structural changes in the extracellular matrix (ECM) of the trabecular meshwork and optic nerve head as characteristically seen in POAG. The changes involve an induction in the expression of various ECM molecules and are remarkably similar in trabecular meshwork cells and optic nerve head astrocytes. The ECM changes in the trabecular meshwork most probably play a role in the increase of aqueous humor outflow resistance causing higher intraocular pressure (IOP). In the optic nerve head, TGF-β2-induced changes might contribute to deformation of the optic nerve axons causing impairment of axonal transport and neurotrophic supply and leading to their continuous degeneration. The increase in IOP further adds mechanical stress and strain to optic nerve axons and accelerates degenerative changes. In addition, high IOP might induce the expression of activated TGF-β1 in trabecular meshwork cells and optic nerve head astrocytes; this again might significantly lead to the progress of axonal degeneration. The action of TGF-β2 in POAG is largely mediated through the connective tissue growth factor, whereas the activities of TGF-β1 and -β2 are modulated by the blocking effects of bone morphogenetic protein-4 (BMP-4) and BMP-7, by gremlin that inhibits BMP signaling and by several species of microRNAs.

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…However, the main source of TGFB2 in AH is either the epithelial layer of the ciliary body (28) or the lens (29). Previous studies have shown that TGFB2 affected the trabecular meshwork, which is an important tissue for draining AH and maintaining normal IOP (30). As complex changes in the trabecular meshwork gradually affect its ability to drain AH from the anterior chamber, it can lead to elevated IOP.…”

A Porcine Ex Vivo Model of Pigmentary Glaucoma

“…According to the pathway modeling, RhoA signaling, the central pathway that regulates the actin cytoskeleton of the TM, is initiated by exposure to pigment via a complex consisting of insulin growth factor (IGF), the type 1 insulin-like growth factor receptor (IGF-IR), and the lysophosphatidic acid receptor (LPAR) in the cell membrane. This is different from the RhoA activation induced by transforming growth factor (TGF)-β and its receptor in primary open-angle glaucoma 69 and steroid glaucoma 70 . In addition to the inhibition of tight junctions by RhoA, upregulation of the rhophilin Rho GTPase binding protein would also promote reorganizing the TM actin cytoskeleton.…”

Common and Rare Genetic Risk Factors for Glaucoma

“…TGF-b I and TGF-b II appear to have important roles in optic nerve degeneration (Zode et al 2009;Fuchshofer 2011) as well as trabecular meshwork function (Sethi et al 2011;Fuchshofer 2012). LTPB2 (associated with congenital glaucoma and anterior segment dysgenesis) and CDKN2BAS (associated with POAG, NTG) are part of the overall TGF-b signaling pathway.…”