Ultrastructure of the Trabecular Meshwork 10in Untreated Cases of Primary Open-Angle Glaucoma (POAG)

Rohen, Johannes W.; Lütjen–Drecoll, Elke; Flügel, Cassandra; Meyer, Michael W.; Grierson, Ian

doi:10.1006/exer.1993.1085

Cited by 180 publications

(118 citation statements)

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“…In support of our proposal are the electron microscopic findings from biopsies of nontreated MYOC-caused glaucoma patients showing a reduction of TM cells as well as thickened trabeculae and accumulation of sheath-derived plaques and of melanin. 36,39,40 The present data point to an important pathogenetic role of mutant MYOC and Russell body formation in the development of elevated IOP in POAG. …”

Section: Discussionsupporting

confidence: 53%

“…3,17,[35][36][37][38][39] Furthermore, a reduction of the number of TM cells has been observed in glaucoma patients. 36,40 Although mutant MYOC singly expressed in different cell types has been shown to be cytotoxic, 25,26,30 its mechanism of action remains elusive. The possible cytotoxicity of heteromeric mutant/WT MYOC complexes whose formation is the basis for the pathological gain-of-function mechanism has not been addressed yet.…”

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confidence: 99%

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Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

114

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Primary open-angle glaucoma with elevated intraocular pressure is a leading cause of blindness worldwide. Mutations of myocilin are known to play a critical role in the manifestation of the disease. Misfolded mutant myocilin forms secretion-incompetent intracellular aggregates. The block of myocilin secretion was proposed to alter the extracellular matrix environment of the trabecular meshwork, with subsequent impediment of aqueous humor outflow leading to elevated intraocular pressure. However, the molecular pathogenesis of myocilin-caused glaucoma is poorly defined. In this study, we show that heteromeric complexes composed of wild-type and mutant myocilin were retained in the rough endoplasmic reticulum, aggregating to form inclusion bodies typical of Russell bodies. The presence of myocilin aggregates induced the unfolded protein response proteins BiP and phosphorylated endoplasmic reticulum-localized eukaryotic initiation factor-2␣ kinase (PERK) with the subsequent activation of caspases 12 and 3 and expression of C/EBP homologous protein (CHOP)/GADD153, leading to apoptosis. Our findings identify endoplasmic reticulum stress-induced apoptosis as a pathway to explain the reduction of trabecular meshwork cells in patients with myocilincaused glaucoma. As a consequence, the phagocytotic capacity of the remaining trabecular meshwork cell population would be insufficient for effective cleaning of aqueous humor, constituting a major pathogenetic factor for the development of Glaucoma is a heterogeneous group of optic neuropathies characterized by a progressive degeneration of the optic nerve resulting in an irreversible loss of vision. 1After age-related macular degeneration, it is the second leading cause of severe vision loss or blindness.2 It is expected that ϳ4% of the world population older than the age of 40 will develop glaucoma. Primary open-angle glaucoma (POAG) is the most common form of the disease.2 In most cases of POAG, the aqueous humor outflow from the anterior eye chamber is impeded, resulting in an elevated intraocular pressure (IOP) and causing ganglion cell death in the neural retina.3,4 Hence, impaired outflow drainage along the trabecular meshwork (TM) and Schlemm's canal seems to be central in the pathogenesis of POAG. 3,4

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Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

114

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“…(Segawa 1979;Lütjen-Drecoll et al 1981;Rohen 1983;Lütjen-Drecoll et al 1986;Lütjen-Drecoll and Tamm 1987;Lutjen-Drecoll and Rohen 2001) The exact molecular nature of this material is not clear and a direct causal link to the increased outflow resistance has been difficult to establish. An additional caveat to these glaucoma studies is that, with few exceptions, (Rohen et al 1993) the tissue is from eyes that have been on various glaucoma medications for extended periods. None the less, valuable information can be gleaned from such studies.…”

Section: Glaucoma and Ecmmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

408

443

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The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

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“…The turnover and remodelling of the TM ECM is regulated by several substrate specific MMPs including interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinases A (MMP-2) and B (MMP-9), as well as the tissue inhibitors of metalloproteinases (TIMPs). 33,34 The accumulation of excess ECM in the glaucomatous TM contributes to restriction of aqueous outflow and subsequent elevation of IOP; 35,36 therefore, one pathway of laser-mediated IOP reduction may lie in stimulating the removal of impeding ECM via MMP-generated remodelling, a process known to increase outflow facility. Several studies using cultured TM cells and explant organ cultures have found expression of MMP-9, its inhibitor TIMP-1 and MMP-3 to increase following ALT, although the levels of MMP-2 and its inhibitor TIMP-2 remain unchanged.…”

Section: Induction Of Matrix Metalloproteinasesmentioning

confidence: 99%

Mechanisms of selective laser trabeculoplasty: a review

Kagan

Gorfinkel

Hutnik

2014

Clinical Exper Ophthalmology

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Selective laser trabeculoplasty is a safe and effective treatment for glaucoma, with greater cost effectiveness than its pharmacological and surgical alternatives. Nevertheless, although the basic science literature on selective laser trabeculoplasty continues to grow, there remains uncertainty over the mechanism by which laser trabeculoplasty reduces intraocular pressure. To address this uncertainty, the evidence behind several potential biological and mechanical mechanisms of selective laser trabeculoplasty were reviewed. In particular, cytokine secretion, matrix metalloproteinase induction, increased cell division, repopulation of burn sites and macrophage recruitment were discussed. Refining our understanding of these mechanisms is essential both to understanding the pathophysiology of ocular hypertension and developing improved therapies to treat the condition.

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Ultrastructure of the Trabecular Meshwork 10in Untreated Cases of Primary Open-Angle Glaucoma (POAG)

Cited by 180 publications

References 0 publications

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Extracellular matrix in the trabecular meshwork

Mechanisms of selective laser trabeculoplasty: a review

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