MiR-18a-5p Targets Connective Tissue Growth Factor Expression and Inhibits Transforming Growth Factor β2-Induced Trabecular Meshwork Cell Contractility

John Knox, George Bou-Gharios, Kevin J Hamill, Colin E Willoughby

Research output: Contribution to journalArticlepeer-review

Abstract

Increased trabecular meshwork (TM) cell and tissue contractility is a driver of the reduced outflow facility and elevation of intraocular pressure (IOP) associated with primary open-angle glaucoma (POAG). Connective tissue growth factor (CTGF) is an established mediator of TM cell contractility, and its expression is increased in POAG due to transforming growth factor β 2 (TGFβ2) signalling. Inhibiting CTGF upregulation using microRNA (miRNA) mimetics could represent a new treatment option for POAG. A combination of in silico predictive tools and a literature review identified a panel of putative CTGF-targeting miRNAs. Treatment of primary human TM cells with 5 ng/mL TGFβ2 for 24 h identified miR-18a-5p as a consistent responder, being upregulated in cells from five different human donors. Transfection of primary donor TM cells with 20 nM synthetic miR-18a-5p mimic reduced TGFβ2-induced CTGF protein expression, and stable lentiviral-mediated overexpression of this miRNA reduced TGFβ2-induced contraction of collagen gels. Together, these findings identify miR-18a-5p as a mediator of the TGFβ2 response and a candidate therapeutic agent for glaucoma via its ability to inhibit CTGF-associated increased TM contractility.
Original languageEnglish
Article number1500
JournalGenes
Volume13
Issue number8
Early online date22 Aug 2022
DOIs
Publication statusE-pub ahead of print - 22 Aug 2022

Keywords

  • Humans
  • MicroRNAs - genetics - metabolism
  • Trabecular Meshwork - metabolism
  • connective tissue growth factor (CTGF)
  • glaucoma
  • microRNAs
  • primary open-angle glaucoma
  • therapeutics
  • trabecular meshwork
  • Transforming Growth Factor beta2 - genetics - pharmacology
  • Glaucoma, Open-Angle - genetics
  • intraocular pressure
  • Connective Tissue Growth Factor - genetics - metabolism
  • TGFβ

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