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.

The Effects of Mechanical Stretch on Integrins and Filopodial-Associated Proteins in Normal and Glaucomatous Trabecular Meshwork Cells

“…A major risk factor of glaucoma is elevated intraocular pressure (IOP), which is caused by dysfunction in the trabecular meshwork (TM) aqueous humor drainage pathway (Stamer and Acott, 2012). The extracellular matrix (ECM) of TM tissue is a source of outflow resistance and glaucomatous ECM differs in amount, structure and organization compared to normal TM tissue (Fuchshofer and Tamm, 2009;Tektas and Lutjen-Drecoll, 2009;Vranka et al, 2015;Acott et al, 2021;Keller and Peters, 2022). Glaucomatous TM tissue has altered biomechanics compared to age-matched tissue derived from non-glaucomatous TM tissue (Last et al, 2011;Raghunathan et al, 2018) Notably, glaucoma TM cells in culture display molecular memory and synthesize and assemble dysfunctional matrices similar to those found in situ (Raghunathan et al, 2018;Acott et al, 2021;Wirtz et al, 2021).…”

Viscoelastic Biomechanical Properties of the Conventional Aqueous Outflow Pathway Tissues in Healthy and Glaucoma Human Eyes

“…When they elevated the pressure to 17.6 mmHg, the elastic modulus of the TM in the LF region is 30.33 kPa while in the HF region is 2.72 kPa [ 58 , 134 ]. Keller similarly showed that the HF regions have a lower elastic modulus and are more compliant than the LF regions [ 135 ]. Our results are in very good agreement with Vranka and Keller, as we found larger short- and long-time shear moduli for the LF regions compared to the HF regions ( Table 3 and Table 4 ), so the HF regions are more compliant and dynamic in their homeostatic response to elevated pressure.…”

TIPARP is involved in the regulation of intraocular pressure

“…We found that a variety of genes associated with ECM and focal adhesion were downregulated in the TIPARP -overexpressing HTM cells by RNA-seq. Previous studies have demonstrated that the trabecular meshwork regulates aqueous humor outflow resistance by cells and their ECM interplay and ECM protein interactions 5 , 6 . Abnormal changes in the ECM have dramatic effects on trabecular meshwork function 22 , 23 .…”

“…IOP is determined by the balance between aqueous humor secretion and drainage mainly through the conventional outflow pathway consisting of the trabecular meshwork, juxtacanalicular tissue and Schlemm's canal 2,3 . Abnormally high resistance to aqueous humor outflow induced by trabecular meshwork malfunction is an important aetiology of POAG [4][5][6] . However, the underlying molecular and cellular mechanisms of increased resistance to aqueous humor outflow still need to be explored.…”