Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma

Abstract

While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.

Histological investigation of human glaucomatous eyes: Extracellular fibrotic changes and galectin 3 expression in the trabecular meshwork and optic nerve head

“…This suggests that TGFβ2 signaling occurs in the TM and optic nerve MTZ of glaucomatous eyes, hence promoting tissue remodeling and/or fibrosis. This is consistent with previous studies (Tamm and Fuchshofer, ; Tovar‐Vidales et al, ; Zode et al, ; Zhavoronkov et al, ). Additionally, Gal3 may also respond to glaucomatous stress in the eye, but this relationship is not entirely clear, as our correlation was not statistically significant.…”

Lowered Decorin With Aberrant Extracellular Matrix Remodeling in Aqueous Humor and Tenon's Tissue From Primary Glaucoma Patients

“…Enormous evidence suggests that there is an aberrant accrual of ECM components in TM, AH, ONH, and lamina cribrosa (LC) attributing to the pathology in glaucoma. [29][30][31][32] Tenon's fibroblasts are the primary effector cells in the initiation and mediation of wound healing and fibrotic scar formation posttrabeculectomy. 33 In our gene and protein expression study, we found evident elevations of genes, that is, MCP-1, CTGF, TGF-b1/2, LOX, LOXL2, ELN, COL1A1, SPARC, and a-SMA compared with cataract control in POAG and PACG.…”

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

“…8). MMPs play a central role in ECM turnover, which reduces resistance to aqueous outflow and can serve as a counter-mechanism to IOP elevation (Zhavoronkov et al, 2016). In light of above studies, it is likely that caveolins and the PI3K-Akt pathway plays a pivotal role in TM physiology and contribute to the pathogenesis of POAG and OHT.…”