Full title: The canonical Wnt signaling pathway inhibits the glucocorticoid receptor signaling pathway in the trabecular meshwork

Abstract Glucocorticoid-induced glaucoma (GIG) is a secondary open angle glaucoma. About 40% of the general population may develop elevated intraocular pressure (IOP) upon prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates IOP. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension (OHT) is crucial. In this study, elevated Dkk1, a canonical Wnt signaling inhibitor, was found in the aqueous humor and trabecular meshwork (TM) of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, while Dkk1 knock down or Wnt signaling activators decreased GR signaling in human TM cells using luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix (ECM) was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced ECM proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced OHT in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators have the potential to prevent the side effect of glucocorticoids in the eye.