Effect of excess synthesis of extracellular matrix components by trabecular meshwork cells: Possible consequence on aqueous outflow

Tane, Nobuhiro; Dhar, Sonya; Roy, Soma; Pinheiro, André Araújo; Ohira, Akihiro; Roy, Sayon

doi:10.1016/j.exer.2007.01.002

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…Abnormal accumulation of ECM components, such as glycosaminoglycans, collagens, fibronectin, and elastin, is hypothesized to cause resistance against aqueous humor outflow. [6][7][8][9] Thus, our results suggested that DEX-induced alterations in ECM production may be partially affected by the RhoA/ROCK signaling pathway.…”

Section: Discussionmentioning

confidence: 74%

“…8,9 Our results showed that selective ROCK inhibition blocked the increased COL4A1and fibronectin mRNA expression, suggesting that the RhoA/ROCK signaling pathway is related to the DEX-induced changes in aqueous outflow. Abnormal accumulation of ECM components, such as glycosaminoglycans, collagens, fibronectin, and elastin, is hypothesized to cause resistance against aqueous humor outflow.…”

Section: Discussionmentioning

confidence: 75%

“…8,9 Therefore, we next quantified the expression levels for COL1A1, COL4A1, and fibronectin mRNAs in cultured porcine TM cells following treatment with DEX and/or Y-27632. Expression of COL4A1 mRNA was increased in cells stimulated with 100 nM DEX, but not in cells treated with 10 lM Y-27632 alone or in cells treated with 10 lM Y-27632 þ 100 nM DEX.…”

Section: Changes In Extracellular Matrix and Integrin Mrna Expressionmentioning

confidence: 99%

“…Some researchers attribute the decreased outflow to an accumulation of extracellular matrix (ECM) components, such as glycosaminoglycans, collagens, fibronectin, and elastin. [6][7][8][9] Others have proposed that the decreased outflow is due to decreased phagocytic function by trabecular meshwork (TM) cells, 10,11 which results in the accumulation of trabecular debris. Clark et al recently reported that exposure of cultured TM cells to steroids induces a reorganization of the cytoskeleton to form cross-linked actin networks.…”

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confidence: 99%

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Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Fujimoto

Inoue

Kameda

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We investigated the involvement of the RhoA/Rho kinase (ROCK) signal transduction pathway in dexamethasone (DEX)-induced changes in aqueous outflow.METHODS. Using trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells, RhoA activation was evaluated with a pull-down assay and myosin light chain phosphorylation was evaluated by Western blot analysis. Outflow facility was measured in perfused porcine anterior segment organ cultures treated with DEX and/or Y-27632, a selective ROCK inhibitor. The barrier function of the cultured cells on a micropore filter was evaluated by measuring the transendothelial electrical resistance. Collagen, fibronectin, and integrin mRNA expression levels were evaluated by quantitative realtime RT-PCR. RESULTS.Relative RhoA activities increased following stimulation with 100 nM DEX in TM and SCE cells. Perfusion with DEX decreased outflow facility by 31.9 6 14.3% compared to controls at 24 hours, but not by 50 lM Y-27632 in addition to DEX. The transendothelial electrical resistance of the SCE cell monolayer was increased by 48.6 6 6.4% and 5.3 6 5.0% following DEX treatments without and with 10 lM Y-27632, respectively, compared to controls. In TM cells, the mRNA expressions of COL4A1 and fibronectin were increased significantly by DEX treatment, but combined treatment with Y-27632 and DEX significantly inhibited the increase in COL4A1and fibronectin expression.CONCLUSIONS. Activation of the Rho/ROCK pathway in SCE cells contributes to the mechanism of DEX-induced changes in aqueous outflow. (Invest Ophthalmol Vis Sci. 2012;53:7097-7108) DOI:10.1167/iovs.12-9989 S teroid-induced ocular hypertension is an important clinical problem related to the use of glucocorticoid therapy for many types of disorders. Already in 1963, Armaly reported that the widely used glucocorticoid dexamethasone (DEX) induces changes in intraocular pressure (IOP) and fluid dynamics in normal eyes, and that DEX-induced IOP elevation is observed more frequently in the patients with glaucoma. 1-3 IOP levels often are quite high in patients with steroid-induced ocular hypertension, and prolonged IOP elevation sometimes results in the loss of visual function. Topical administration of triamcinolone acetonide (TA), a synthetic corticosteroid, is considered a useful therapeutic modality for the management of intraocular inflammatory and/or proliferative diseases. The increasing number of patients treated with TA by intravitreous and/or sub-Tenon injections, however, has attracted the attention of ophthalmologists because of the potential risk of steroid-induced ocular hypertension. 4,5The mechanisms underlying steroid-induced ocular hypertension are associated with abnormal changes in the conventional outflow pathway caused by steroid administration. Some researchers attribute the decreased outflow to an accumulation of extracellular matrix (ECM) components, such as glycosaminoglycans, collagens, fibronectin, and elastin. [6][7][8][9] Others have proposed that the decreased outflow is due to decrea...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 75%

Section: Changes In Extracellular Matrix and Integrin Mrna Expressionmentioning

confidence: 99%

mentioning

confidence: 99%

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Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Fujimoto

Inoue

Kameda

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…[37][38][39][40] In monolayers of TM endothelial cells, high glucose and dexamethasone each induced collagen type IV and laminin, changes resulting in decreased permeability. 41 In ex vivo porcine eyes, overexpression of a constitutively active mutant form of RhoA GTPase increased IOP through greater contractility of inner wall SC cells and increased JCT collagen type IV, fibronectin, and laminin. 42 The increase of JCT basement membrane material seen in our experiments correlates with compromised TM drainage and is likely a significant contributor to the mechanism of increased IOP caused by SPARC overexpression.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SPARC in Human Trabecular Meshwork Increases Intraocular Pressure and Alters Extracellular Matrix

Kang

Ooi

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Oh D-J, Kang MH, Ooi YH, Choi KR, Sage EH, Rhee DJ. Overexpression of SPARC in human trabecular meshwork increases intraocular pressure and alters extracellular matrix. Invest Ophthalmol Vis Sci. 2013;54:3309-3319, DOI:10.1167/ iovs.12-11362 PURPOSE. Intraocular pressure (IOP) regulation is largely unknown. SPARC-null mice demonstrate a lower IOP resulting from increased outflow. SPARC is a matricellular protein often associated with fibrosis. We hypothesized that SPARC overexpression would alter IOP by affecting extracellular matrix (ECM) synthesis and/or turnover in the trabecular meshwork (TM).METHODS. An adenoviral vector containing human SPARC was used to increase SPARC expression in human TM endothelial cells and perfused human anterior segments using multiplicities of infection (MOIs) 25 or 50. Total RNA from TM was used for quantitative PCR, while protein from cell lysates and conditioned media were used for immunoblot analyses and zymography. After completion of perfusion, the anterior segments were fixed, sectioned, and examined by light and confocal microscopy.RESULTS. SPARC overexpression increased the IOP of perfused human anterior segments. Fibronectin and collagens IV and I protein levels were elevated in both TM cell cultures and within the juxtacanalicular (JCT) region of perfused anterior segments. Collagen VI and laminin protein levels were increased in TM cell cultures but not in perfused anterior segments. The protein levels of pro-MMP-9 decreased while the kinetic inhibitors of metalloproteinases, TIMP-1 and PAI-1 protein levels, increased at MOI 25. At MOI 50, the protein levels of pro-MMP-1, -3, and -9 also decreased while PAI-1 and TIMP-1 and -3 increased. Only MMP-9 activity was decreased on zymography. mRNA levels of the collagens, fibronectin, and laminin were not affected by SPARC overexpression.CONCLUSIONS. SPARC overexpression increases IOP in perfused cadaveric human anterior segments resulting from a qualitative change the JCT ECM. Selective decrease of MMP-9 activity is likely part of the mechanism. SPARC is a regulatory node for IOP.Keywords: SPARC, adenovirus, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, extracellular matrix, intraocular pressure, perfused anterior segment system P rimary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness.

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How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers

2010

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Effect of excess synthesis of extracellular matrix components by trabecular meshwork cells: Possible consequence on aqueous outflow

Cited by 40 publications

References 48 publications

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Overexpression of SPARC in Human Trabecular Meshwork Increases Intraocular Pressure and Alters Extracellular Matrix

How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers

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