Gene expression in the trabecular meshwork and the influence of intraocular pressure

Borrás, Teresa

doi:10.1016/s1350-9462(03)00018-1

Cited by 79 publications

(68 citation statements)

References 136 publications

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“…[8][9][10][11][12] In the eye, MMPs have a vital role in ECM degradation and remodeling in the TM, which maintains the outflow pathway and IOP homeostasis. [10][11]13,14 Raised IOP induces upregulation of MMPs in TM, which, in turn, increase ECM degradation thereby decreasing outflow resistance. Reversible increase in outflow facility has been demonstrated in vitro by perfusing the human anterior segment organ culture system with recombinant MMP-2 and -9, which was reversed with inhibition of endogenous MMP activity.…”

Section: Discussionmentioning

confidence: 99%

“…15 Laser trabeculoplasty has been demonstrated to cause increased outflow facility, which is postulated to be caused by increasing MMP activity and ECM degradation along with other mechanisms. 8,11,12,14 Most of these earlier studies evaluated MMP expressions in cell culture and animal models, or in aqueous humor of human patients with glaucoma. This study found increased MMP-9 activity in tears and Tenon's capsule with no parallel increase in MMP-2 activity in any POAG, PACG, or PXG eyes suggesting alterations of MMP levels and function at the ocular surface in different form and severities of glaucoma.…”

Section: Discussionmentioning

confidence: 99%

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Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Sahay

Rao

Padhy

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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[PXG]). These were compared to patients undergoing cataract surgery (controls) for this cross-sectional study. Functional activities of tear MMP-9 and MMP-2 were analyzed by gelatin zymography. Tenon's capsules (n ¼ 15) were harvested from the inferior quadrant in those undergoing cataract surgery and protein expression of MMP-9 was analyzed by immunohistochemistry (IHC). Hydrogen peroxide (H 2 O 2 ) stress-induced effects on in vitro activities of MMP-9 in human trabecular meshwork (HTM) cells were analyzed.RESULTS. The MMP-9 activity in tears was increased significantly in POAG, (n ¼ 27), PACG (n ¼ 24), and PXF (n ¼ 40) eyes compared to controls (n ¼ 35), and was increased significantly in eyes with glaucoma compared to moderate/severe glaucoma (P < 0.001). The MMP-9 expression was significantly lower in PXG (n ¼ 22) eyes. Immunohistochemistry of Tenon's capsule revealed increased expression of MMP-9 in primary glaucoma eyes. Increased MMP-9 activity was seen in in vitro by gelatin zymography and was confirmed by Western and immunofluorescent assay on HTM upon 800 and 1000 lM H 2 O 2 -induced stress for 2 to 3 hours with approximately 80% cell death. CONCLUSIONS.Increased tear MMP-9 activity in early glaucoma and pseudoexfoliation syndrome suggesting activation of extracellular matrix (ECM) degradation can be used as a tear-based predictive biomarker. Decreased expression in advanced stages suggests exhaustion of the degradation response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Sahay

Rao

Padhy

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…This includes a number of SLRPs, CSPGs, HSPGs, and other types of PGs (Table 1). (Murphy et al 1987;Tanihara et al 1995;Wirtz et al 1997;Knepper, P et al 1998;Friedman et al 2000;Friedman et al 2002;Ishibashi et al 2002;Knepper, P et al 2002;Borras 2003;Lo et al 2003;Filla et al 2004;Vittitow and Borras 2004;Zhao et al 2004;Chen et al 2005;Vittal et al 2005;Keller et al 2007b) Some specific core proteins have been localized to regions of the TM by immunohistochemistry using light or transmission electron microscopy. Perlecan was localized to the basement membranes of the TM beams and SC inner wall cells.…”

Section: Proteoglycansmentioning

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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“…Other mechanisms proposed as playing important roles in TM function include changes in extracellular matrix (Tian et al, 2000), up-regulation/down-regulation of genes (Borras, 2003), and changes in cell shape (Gills et al, 1998) or cell volume (Al-Aswad et al, 1999;Soto et al, 2004). It is possible that dinucleotides could modify some of these parameters such as cell volume, as proposed for other compounds (Fleischhauer et al, 2003;Srinivas et al, 2004).…”

Section: Dinucleotide Effects In Aqueous Humormentioning

confidence: 99%

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap 4 A) and pentaphosphate (Ap 5 A) in the AH. Topic application of Ap 4 A to the cornea decreased IOP, whereas Ap 5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap n As; n ϭ 3-5) and Up 4 U (P 1 ,P 4 -(diuridine 5Ј)-tetraphosphate; INS365) in outflow facility were tested. P2Y 1 , P2Y 2 , and P2Y 4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap 3 A, Ap 4 A, and Ap 5 A induced discrete intracellular calcium concentration ([Ca 2ϩ ] i ) mobilizations compared with higher and more sustained [Ca 2ϩ ] i mobilizations after Up 4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 M Ap 3 A or Ap 4 A increased outflow facility, whereas Up 4 U or Ap 5 A did not modify it. 2-MeSADP, a selective P2Y 1 agonist, induced outflow facility increases similar to those obtained after Ap 3 A and Ap 4 A, and these were prevented by addition of the selective P2Y 1 receptor antagonist MRS-2179 (2Ј-deoxy-N 6 -methyladenosine-3Ј,5Ј-diphosphate). Our results demonstrate that the hypotensive effect of Ap 4 A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y 1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.In the eye, elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage is a major risk factor in the development of glaucoma. Glaucoma is the most important cause of irreversible nontraumatic blindness in the world and affects more than 66 million people. The main determinant of IOP is the volume of AH contained in the anterior and posterior chambers. AH is produced in the ciliary epithelium and eliminated through the outflow pathways in the anterior chamber angle. In several species, but especially in the primate eye, most AH flows through the trabecular meshwork (TM), a sponge-like filtering tissue, where it reaches Schlemm's canal and the collector channels before finally entering the venous system. The structure of the TM and its ability to modify its resistance to AH outflow play a key role in maintaining the IOP in the anterior chamber within its physiological range. TM cells express several receptors to substances released either in the AH from different ocular tissues (Mitchell et al., 1998;Coca-Prados et al., 1999) or from ocular innervation (Selbach et al., 2000) in physiologic...

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Gene expression in the trabecular meshwork and the influence of intraocular pressure

Cited by 79 publications

References 136 publications

Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Extracellular matrix in the trabecular meshwork

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

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