Pathogenesis of glaucoma: Extracellular matrix dysfunction in the trabecular meshwork-A review

Abstract

The trabecular meshwork regulates aqueous humour outflow from the anterior chamber of the eye. It does this by establishing a tunable outflow resistance, defined by the interplay between cells and their extracellular matrix (ECM) milieu, and the molecular interactions between ECM proteins. During normal tissue homeostasis, the ECM is remodelled and trabecular cell behaviour is modified, permitting increased aqueous fluid outflow to maintain intraocular pressure (IOP) within a relatively narrow physiological pressure. Dysfunction in the normal homeostatic process leads to increased outflow resistance and elevated IOP, which is a primary risk factor for glaucoma. This review delineates some of the changes in the ECM that lead to gross as well as some more subtle changes in the structure and function of the ECM, and their impact on trabecular cell behaviour. These changes are discussed in the context of outflow resistance and glaucoma.

Keywords: extracellular matrix; glaucoma; trabecular meshwork.

FIGURE 1

The conventional and unconventional outflow pathway. Aqueous humour produced by the ciliary body flows into the anterior chamber between the lens and iris. In the conventional pathway, the majority of the aqueous fluid exits the anterior chamber through the trabecular meshwork/Schlemm’s canal (TM/SC) system (black arrows). In the unconventional pathway, aqueous humour exits through the sclera (blue arrows)

FIGURE 2

The trabecular meshwork/Schlemm’s canal outflow pathway. (A) Aqueous humour (AH; green arrows) flows through the uveoscleral meshwork (UM), corneoscleral meshwork (CM) and the juxtacanalicular tissue (JCT). It then crosses the basement membrane (BM) underlying the inner wall of Schlemm’s Canal (SC) to exit either paracellularly and transcellularly into the lumen of SC. Box indicates placement of image show in panel B. (B) Diagram illustrates ECM proteins found in the two layers of the BM and the upper region of the JCT. The BM is divided into the lamina (LM) densa and the LM reticularis. Cellular protrusions extend between JCT cells, and between JCT and SC cells. These protrusions play important roles in detecting alterations in the ECM biomechanical environment and communicating signals between cells. Col; collagen, TSP; thrombospondin, FN, fibronectin; FBN, fibrillin; ELN, elastin; TN, tenascin; PGs, proteoglycans (e.g., versican and hyaluronan); NID-1, nidogen; PLC, perlecan; LM, laminin. Source: Figure was modified from a previously published image Reference

FIGURE 3

Hypothetical scenario how conformation of fibronectin (FN) fibrils affect integrin signalling. (A) The α5β1 integrin can recognise its binding motif in a highly coiled FN fibril, which activates a GTPase signalling pathway that controls ECM formation and phagocytosis. (B) If the fibril is stretched, the α5β1 integrin binding motif in the fibril is conformationally altered preventing the α5β1 integrin from binding FN. The stretching of the fibril, however, reveals a binding motif for the αvβ3 integrin. Activation of the αvβ3 integrin alters the GTPase signalling pathway that controls ECM formation and phagocytosis

FIGURE 4

CD44 and hyaluronan in trabecular meshwork cells. (A) Schematic showing CD44 interactions with hyaluronic acid (HA), intracellular signalling pathways and proteolytic processing. (1) CD44 binds to HA via its extracellular domain and dephosphorylated merlin on its intracellular domain (ICD). This inhibits the Ras–Raf–MEK–ERK signalling cascade. (2) If HA-CD44 interactions are disrupted, CD44 binds to phosphorylated Ezrin-Radixin-Moesin (ERM) complex and phosphorylated Merlin, which activates the Ras–Raf–MEK–ERK signalling cascade and ultimately alters gene transcription. Phosphorylated ERM also bind to actin filaments. (3) The extracellular domain of CD44 can be proteolytically cleaved by proteinases such as MMP14 and ADAM10, which leads to ‘shed’ CD44 (sCD44). sCD44 competes with membrane-bound CD44 for binding to HA. CD44 is also cleaved intracellularly by γ-secretase, which liberates the ICD. This small proteolytic fragment launches a signalling cascade, which ultimately alters gene transcription. (B) HA internalisation by CD44. (1) HA is degraded into small fragments by extracellular hyaluronidases. HA fragments are internalised by CD44 in a clathrin-dependent endocytic mechanism and are degraded in the lysosome. (2) If HA fragments are bound to sCD44, or to other HA-binding proteoglycans (such as versican [VSCN]), uptake by CD44 is sterically hindered. (3) HA-coated nanoparticles can encapsulate a glaucoma drug and they can be internalised by CD44. Once the nanoparticles are degraded, the drug of interest is released intracellularly