Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork

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Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork. / Hill, Lisa J.; Mead, Ben; Blanch, Richard J; Ahmed, Zubair; De Cogan, Felicity; Morgan-Warren, Peter J; Mohamed, Shabbir; Leadbeater, Wendy; Scott, Robert A H; Berry, Martin; Logan, Ann.

In: Investigative Ophthalmology & Visual Science (IOVS), Vol. 56, No. 6, 01.06.2015, p. 3743-57.

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@article{6fa19f9159d94bf7bbc34bca8ff20755,
title = "Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork",
abstract = "PURPOSE: To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.METHODS: Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.RESULTS: Transforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.CONCLUSIONS: Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.",
keywords = "Animals, Cell Death, Decorin, Fibrosis, Intraocular Pressure, Male, Rats, Rats, Sprague-Dawley, Retinal Ganglion Cells, Trabecular Meshwork, TGF-beta, Extracellular Matrix",
author = "Hill, {Lisa J.} and Ben Mead and Blanch, {Richard J} and Zubair Ahmed and {De Cogan}, Felicity and Morgan-Warren, {Peter J} and Shabbir Mohamed and Wendy Leadbeater and Scott, {Robert A H} and Martin Berry and Ann Logan",
note = "Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.",
year = "2015",
month = jun,
day = "1",
doi = "10.1167/iovs.14-15622",
language = "English",
volume = "56",
pages = "3743--57",
journal = "Investigative Ophthalmology & Visual Science (IOVS)",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology",
number = "6",

}

RIS

TY - JOUR

T1 - Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork

AU - Hill, Lisa J.

AU - Mead, Ben

AU - Blanch, Richard J

AU - Ahmed, Zubair

AU - De Cogan, Felicity

AU - Morgan-Warren, Peter J

AU - Mohamed, Shabbir

AU - Leadbeater, Wendy

AU - Scott, Robert A H

AU - Berry, Martin

AU - Logan, Ann

N1 - Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - PURPOSE: To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.METHODS: Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.RESULTS: Transforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.CONCLUSIONS: Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

AB - PURPOSE: To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.METHODS: Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.RESULTS: Transforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.CONCLUSIONS: Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

KW - Animals

KW - Cell Death

KW - Decorin

KW - Fibrosis

KW - Intraocular Pressure

KW - Male

KW - Rats

KW - Rats, Sprague-Dawley

KW - Retinal Ganglion Cells

KW - Trabecular Meshwork

KW - TGF-beta

KW - Extracellular Matrix

U2 - 10.1167/iovs.14-15622

DO - 10.1167/iovs.14-15622

M3 - Article

C2 - 26066743

VL - 56

SP - 3743

EP - 3757

JO - Investigative Ophthalmology & Visual Science (IOVS)

JF - Investigative Ophthalmology & Visual Science (IOVS)

SN - 0146-0404

IS - 6

ER -