Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

O’Callaghan, Jeffrey; Cassidy, Paul; Humphries, Pete

doi:10.1080/14728222.2017.1386174

Cited by 43 publications

(34 citation statements)

References 170 publications

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“…In humans, IOP is primarily controlled by the out‐flow of the AH through the trabecular meshwork (TM), also known as the conventional out‐flow pathway. The TM is a porous structure composed of endothelial cells embedded in a dense extracellular matrix (ECM), composed of collagen, elastic fibres, proteoglycans and other macromolecules . Fibrotic changes or deposits of ECM into the TM can slow or block the out‐flow which leads to an elevation of the IOP .…”

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicle‐mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling

Lerner

Schreiber‐Avissar

Beit‐Yannai

2020

J Cellular Molecular Medi

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Primary open-angle glaucoma is a leading cause of irreversible blindness, often associated with increased intraocular pressure. Extracellular vesicles (EVs) carry a specific composition of proteins, lipids and nucleotides have been considered as essential mediators of cell-cell communication. Their potential impact for crosstalk between tissues responsible for aqueous humour production and out-flow is largely unknown.The study objective was to investigate the effects of EVs derived from non-pigmented ciliary epithelium (NPCE) primary cells on the expression of Wnt proteins in a human primary trabecular meshwork (TM) cells and define the mechanism underlying exosome-mediated regulation that signalling pathway. Consistent with the results in TM cell line, EVs released by both primary NPCE cells and NPCE cell line showed diminished pGSK3β phosphorylation and decreased cytosolic levels of β-catenin in primary TM cells. At the molecular level, we showed that NPCE exosome treatment downregulated the expression of positive GSKβ regulator-AKT protein but increased the levels of GSKβ negative regulator-PP2A protein in TM cells. NPCE exosome protein analysis revealed 584 miRNAs and 182 proteins involved in the regulation of TM cellular processes, including WNT/β-catenin signalling pathway, cell adhesion and extracellular matrix deposition. We found that negative modulator of Wnt signalling miR-29b was abundant in NPCE exosomal samples and treatment of TM cells with NPCE EVs significantly decreased COL3A1 expression. Suggesting that miR-29b can be responsible for decreased levels of WNT/β-catenin pathway. Overall, this study highlights a potential role of EVs derived from NPCE cells in modulating ECM proteins and TM canonical Wnt signalling. K E Y W O R D S exosomes, extracellular matrix, extracellular vesicles, non-pigmented ciliary epithelium, primary open-angle glaucoma, trabecular meshwork, Wnt | 4647 LERNER Et aL.

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Section: Introductionmentioning

confidence: 99%

“…Fibrotic changes or deposits of ECM into the TM can slow or block the out‐flow which leads to an elevation of the IOP . Glaucoma is thus linked to TM structure and function where structural changes in the TM likely alter tissue architecture and biomechanical properties which, in turn, influence its resistance to AH out‐flow …”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle‐mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling

Lerner

Schreiber‐Avissar

Beit‐Yannai

2020

J Cellular Molecular Medi

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“…33 The ECM of the juxtacanalicular region participates in the generation of resistance to aqueous humor outflow through the TM pathway. 31 The ECM of the TM consists of collagens, laminins, elastin, fibronectin, fibrillins, and proteoglycans 34 and is continuously being remodeled by members of the MMP family (eg, MMP-1, -2, -3, -9, -12, and -14). 12 Studies using perfused human anterior segment organ cultures and human TM cell cultures have shown that increases in IOP cause an increase in MMP-2 expression, and mechanical stretching of TM cells causes an increase in MMP-2 expression and a decrease in TIMP-2 expression.…”

Section: Glaucoma Aqueous Outflow Pathways and Mmpsmentioning

confidence: 99%

Matrix Metalloproteinases and Glaucoma Treatment

Weinreb

Robinson

Dibas

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

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Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect. IOP, intraocular pressure; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; TIMP, tissue inhibitor of metalloproteinase.MMPS AND GLAUCOMA TREATMENT 209 210 WEINREB ET AL.

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“…Increased intraocular pressure is considered to be the most important risk factor for the incidence and progression of glaucoma [4,[7][8][9]]. An imbalance between aqueous humor secretion in the ciliary body (CB) and outflow in the anterior chamber angle mainly due to increased outflow resistance is responsible for the increased IOP in glaucoma [10,11]. However, little is known about the exact mechanisms of IOP regulation.…”

Section: Discussionmentioning

confidence: 99%

A Study on the intraocular pressure of the affected and unaffected eyes in patients with isolated cranial nerve palsies

Dikmetaş

Voykov

2020

Acta Medica

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Objective: The role of elevated intraocular pressure (IOP) in the incidence and progression of glaucoma is well known. However, the exact mechanisms of IOP regulation are still unclear. Central IOP control has been suggested, but the autonomic pathway through which it acts is not known. The aim of this study was to investigate if isolated cranial nerve (CN) palsies of the third, fourth and sixth nerves are associated with an IOP difference between the affected and the unaffected eyes. Materials and Methods: This was a retrospective study including patients diagnosed with a third, fourth and sixth nerve palsy at a single tertiary centre. We included only patients with an isolated unilateral palsy. Patients with a history of strabismus, orbital disease or neurosurgical cases were excluded. Results: The charts of 1712 patients were reviewed. Third, fourth and sixth nerve palsies were found in 469 patients, 314 patients and 929 patients, respectively. Of all patients, 190 (10.6%) were eligible for inclusion in the study. A third nerve, fourth nerve or sixth nerve palsy was present in 85 (44.7%), 65 (34.2%) and 40 (21.1%) patients, respectively. The mean IOP of the affected eyes and the unaffected eyes was not statistically significant different: 14.1 ± 3.1 mmHg vs. 14.6 ± 2.7 mmHg in the CN3 group (p=0.087); 13.6 ± 2.6 mmHg vs. 13.7 ± 2.3 mmHg in the CN4 group (p=0.69); and 14.3 ± 2.7 mmHg vs. 14.9 ± 3.3 mmHg in the CN6 group (p=0.089). There was no statistically significant difference between the mean IOP differences of the affected and unaffected eyes among the three groups (p=0.47). Conclusion: Our study demonstrated no difference in IOP between affected and unaffected eyes in patients with an isolated cranial nerve palsy. These findings are the first and important for ophthalmology practice.

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Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

Cited by 43 publications

References 170 publications

Extracellular vesicle‐mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling

Extracellular vesicle‐mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling

Matrix Metalloproteinases and Glaucoma Treatment

A Study on the intraocular pressure of the affected and unaffected eyes in patients with isolated cranial nerve palsies

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