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Decorin reduces itraocular 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 and Logan, Ann 2015. Decorin reduces itraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork. Investigative Ophthalmology & Visual Science 56 (6) , pp. 3743-3757. 10.1167/iovs.14-15622

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
ISSN: 0146-0404
Date of First Compliant Deposit: 15 November 2019
Last Modified: 20 Nov 2019 14:34
URI: http://orca.cf.ac.uk/id/eprint/126605

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