The Role of TGF-β2 and Bone Morphogenetic Proteins in the Trabecular Meshwork and Glaucoma

Abstract

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a primary risk factor associated with POAG. Increased aqueous humor (AH) outflow resistance through the trabecular meshwork (TM) results in elevated IOP in POAG patients. Resistance to AH outflow is associated with increased accumulation of extracellular matrix (ECM) proteins in the TM. In addition, levels of transforming growth factor-beta2 (TGF-β2) are elevated in the AH and TM tissue of POAG patients. Elevated levels of TGF-β2 in other tissues have been associated with fibrosis and increased tissue stiffness. However, locally produced effectors that maintain homeostatic relationships must also be present. Bone morphogenetic proteins (BMPs) serve this purpose in the TM as they inhibit TGF-β2-induced ECM changes in TM cells. This review article first describes the TGF-β superfamily of growth factors including BMPs and their canonical and noncanonical signaling pathways. The article then addresses the role of TGF-β2 in the pathophysiology of POAG as related to the ECM and ECM crosslinking enzymes. This is followed by a discussion of potential homeostatic control mechanisms of TGF-β2 signaling in the TM including the inhibitory role of BMP-4 and BMP-7. We then describe the relationship of TGF-β2 and BMPs in TM fibrosis including the role of antagonists. Lastly, in future directions, we identify potential future studies that explore new and unique cellular interactions within the TM for potential therapeutic interventions.

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

“…We also examined Tgfb2 gene expression in the retina because of its previously described association with human primary open angle glaucoma (POAG) (11)(12)(13) and because GDF15 is a member of the TGF-β superfamily (14). In terms of rodent models of glaucoma, no rodent glaucoma model has convincingly demonstrated elevated Tgfb2 gene expression in the retina.…”

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

“…Studies of TGFβ2 signaling via both canonical and non-canonical pathways, bone morphogenetic protein (BMP)-family counter regulation, BMP antagonists like gremlin, and associated complex interactions have been described and reviewed in detail elsewhere (Fuchshofer and Tamm, 2012; Fuchshofer et al, 2007; Sethi et al, 2011a; Wordinger et al, 2007; Wordinger et al, 2014). One effect of TGFβ2 treatment is an increase in the matricellular protein, connective tissue growth factor (CTGF).…”

Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction

“…Exposure of conventional outflow tissues to TGFβ results in increased outflow resistance and increased accumulation of fibrillar material in the JCT, reminiscent of glaucoma (Fleenor et al, 2006; Gottanka et al, 2004; Shepard et al, 2010). The molecular mechanisms that underlie increased resistance appear in part to be mediated by bone morphogenic protein-1, which activates cross-linking enzymes (LOX and LOXL1), resulting in resistance to matrix degradation and increased tissue stiffness (Wordinger et al, 2014). …”