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

Abstract

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by b-catenin knockdown increased glucocorticoidinduced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

Glucocorticoids Preferentially Influence Expression of Nucleoskeletal Actin Network and Cell Adhesive Proteins in Human Trabecular Meshwork Cells

“…It is well recognized that glucocorticoid-induced IOP is associated with changes in actin cytoskeletal organization, actin crosslinking, cell-ECM adhesion, cell–cell junctions, ECM accumulation, and cell stiffness in TM cells ( Underwood et al, 1999 ; Raghunathan et al, 2015 ; Bermudez et al, 2017a ; Filla et al, 2017 ). Signaling (including integrins, Rho and Rac GTPases, syndican-4 and Wnt) ( Filla et al, 2011 ; Fujimoto et al, 2012 ; Sugali et al, 2021 ), transcriptional (e.g., Yap/Taz) ( Peng et al, 2018 ), and epigenetic (e.g., DNA methylation) ( Matsuda et al, 2015 ) pathways are reported to be involved in some of these glucocorticoid-induced cellular and IOP changes. Our understanding of the identity of molecular mechanisms underlying the regulation of actin cytoskeletal reorganization and assembly in TM cells by glucocorticoids however, remains elusive ( Bermudez et al, 2017a ).…”

Short and long-term effect of dexamethasone on the transcriptome profile of primary human trabecular meshwork cells in vitro

“…In a recent study, it is shown that GR and WNT signaling inhibit each other in the TM, and that activation of Wnt signaling could prevent the adverse effect of glucocorticoids in the eye 47 . In the above study, elevated levels of Dickkopf-related protein1 (Dkk1) which is a canonical Wnt signaling inhibitor was found in the aqueous humor and TM of glaucoma patients.…”

MYOC/p.G367R mutation induces cell dysfunction of the trabecular meshwork and retina via impairment of the protein degradation mechanism

“…Previous studies reported that myocilin regulates cytoskeletal arrangement and ECM protein production via the Wnt signaling pathway. [22,23] However, we did not detect changes in the mRNA expression of key molecules of the Wnt signaling pathway, including Axin2, sFRP1 and DKK1 (Fig. 2D).…”

“…Wnt signaling molecules are expressed in the TM and regulate dexamethasone-mediated TM cell dysfunctions, including impairment of cytoskeletal arrangement and bronectin production. [22,23] Interestingly, myocilin and Wnt signaling molecules possess similar downstream pathways, and mutual regulation between myocilin and Wnt exists. [38,39] However, MYOC/p.G367R mutation did not change Wnt transcript expression, cytoskeletal arrangement or bronectin production.…”