The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork

Area of Science:

• Ophthalmology
• Molecular Biology
• Cell Biology

Background:

• Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma.
• Elevated intraocular pressure (IOP) affects ~40% of individuals on prolonged glucocorticoid treatment.
• Damage to the trabecular meshwork (TM) by glucocorticoids impairs IOP regulation.

Purpose of the Study:

• Identify key molecules involved in glucocorticoid-induced ocular hypertension.
• Investigate the interplay between Wnt and glucocorticoid receptor (GR) signaling in the TM.
• Explore Wnt signaling activators as a potential therapeutic approach.

Main Methods:

• Measured Dickkopf-related protein 1 (Dkk1) levels in aqueous humor and TM.
• Utilized luciferase assays in human TM cells to assess signaling pathways.
• Employed Wnt activators, Dkk1 knockdown, and β-catenin knockdown.
• Administered adenovirus-mediated Wnt3a to mouse eyes.

Main Results:

• Dkk1, a Wnt inhibitor, was elevated in glaucoma patients.
• Dkk1 enhanced GR signaling; Wnt activation or Dkk1 knockdown decreased GR signaling.
• GR activation inhibited Wnt signaling.
• Wnt activation or Dkk1 knockdown reduced glucocorticoid-induced extracellular matrix proteins.
• Wnt3a expression decreased ocular hypertension in mice.

Conclusions:

• Wnt and GR signaling pathways mutually inhibit each other in the TM.
• Canonical Wnt signaling activators may prevent adverse glucocorticoid effects on the eye.
• Targeting Wnt signaling presents a promising strategy for managing glucocorticoid-induced ocular hypertension.