TGF-beta/OPTN/FOXC1/miR-200 axis regulates intraocular pressure dynamics in trabecular meshwork cells

Abstract

Glaucoma is the second leading cause of irreversible blindness globally, with elevated intraocular pressure (IOP) being its primary risk factor. Current therapeutic approaches, such as beta-blockers, alpha-adrenergic agonists, Rho-kinase inhibitors, etc., aim to reduce IOP levels. However, the molecular mechanisms underlying altered IOP remain poorly understood. In this study, we have treated primary human trabecular meshwork cells (HTM) with exogenous dexamethasone (dex) or transforming growth factor beta-2 (TGF-{beta}2) to investigate its effects on glaucoma candidate genes. Interestingly, our findings reveal that FOXC1 acts as a repressor to CYP1B1, and optineurin (OPTN) facilitates the ubiquitination of FOXC1, thereby inducing CYP1B1 expression. Further, we discovered that the miR-200 family and other miRNAs regulate these glaucoma-candidate genes. Furthermore, TGF-{beta}2 downregulates the miR-200 family, whereas the miR-200 family targets FOXC1, exerting reversible effects by altering the extracellular matrix. FOXC1 positively regulates CLOCK, one of its target genes. Besides, CLOCK/BMAL1 has binding sites on miR-200 family promoters. Modulating the TGF-{beta}2/OPTN/FOXC1/miR-200 axis appears critical in regulating IOP dynamics through CLOCK/BMAL1-mediated daily rhythmicity in the anterior segment of the eye. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/593675v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1c1fb5eorg.highwire.dtl.DTLVardef@5de067org.highwire.dtl.DTLVardef@1378e7borg.highwire.dtl.DTLVardef@6b53d1_HPS_FORMAT_FIGEXP M_FIG C_FIG