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

Lisa J. Hill*, Ben Mead, Richard J. Blanch, Zubair Ahmed, Felicity De Cogan, Peter J. Morgan-Warren, Shabbir Mohamed, Wendy Leadbeater, Robert A.H. Scott, Martin Berry, Ann Logan

*Corresponding author for this work

Research output: Contribution to journalArticle

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 (30d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21d and 30d. 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 17d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30d. Decorin treatment from 17d 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.

Original languageEnglish
Pages (from-to)3743-3757
Number of pages15
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

Fingerprint

Decorin
Trabecular Meshwork
Retinal Ganglion Cells
Intraocular Pressure
Rodentia
Fibrosis
Extracellular Matrix
Injections
Cell Death
Evoked Potentials
Tissue Inhibitor of Metalloproteinases
Visual Pathways
Matrix Metalloproteinase Inhibitors
Open Angle Glaucoma
Transforming Growth Factors
Matrix Metalloproteinases
Cell Survival
Therapeutics

Bibliographical note

Creative Commons Attribution Non-Commercial No Derivatives License

Keywords

  • Decorin
  • Extracellular matrix
  • Fibrolysis
  • Intraocular pressure
  • TGF-β
  • Trabecular meshwork

Cite this

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. / Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 6. pp. 3743-3757.
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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 (30d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21d and 30d. 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 17d, responses that were associated with 42{\%} RGC loss and a significant decrease in VEP amplitude measured at 30d. Decorin treatment from 17d 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.",
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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",
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Hill, LJ, Mead, B, Blanch, RJ, Ahmed, Z, De Cogan, F, Morgan-Warren, PJ, Mohamed, S, Leadbeater, W, Scott, RAH, Berry, M & Logan, A 2015, 'Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork', Investigative Ophthalmology and Visual Science, vol. 56, no. 6, pp. 3743-3757. https://doi.org/10.1167/iovs.14-15622

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 and Visual Science, Vol. 56, No. 6, 01.06.2015, p. 3743-3757.

Research output: Contribution to journalArticle

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 - Creative Commons Attribution Non-Commercial No Derivatives License

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 (30d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21d and 30d. 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 17d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30d. Decorin treatment from 17d 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 (30d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21d and 30d. 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 17d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30d. Decorin treatment from 17d 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 - Decorin

KW - Extracellular matrix

KW - Fibrolysis

KW - Intraocular pressure

KW - TGF-β

KW - Trabecular meshwork

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