Inhibition by a retinoic acid receptor γ agonist of extracellular matrix remodeling mediated by human Tenon fibroblasts

PURPOSE: Scar formation is most frequently responsible for the failure of glaucoma filtration surgery. Retinoic acids are vitamin A derivatives that play diverse roles in development, immunity, and tissue repair. The effects of the retinoic acid receptor (RAR) γ agonist R667 on the contractility of human Tenon fibroblasts (HTFs) cultured in a three-dimensional collagen gel as well as on intraocular pressure (IOP) in a rat model of glaucoma filtration surgery were investigated. METHODS: HTFs were cultured in a type I collagen gel, the contraction of which was evaluated by measurement of the gel diameter. The release of matrix metalloproteinases (MMPs) into culture supernatants was assessed with immunoblot analysis and gelatin zymography. Phosphorylation of focal adhesion kinase (FAK) was examined with immunoblot analysis, and production of fibronectin and type I collagen was measured with immunoassays. RESULTS: R667 inhibited transforming growth factor-β1 (TGF-β1)-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner, whereas an RARα agonist inhibited this process to a lesser extent and an RARβ agonist had no effect. TGF-β1-induced MMP-1 and MMP-3 release, FAK phosphorylation, and fibronectin and type I collagen production in HTFs were also attenuated by R667. Furthermore, R667 lowered IOP in rats after glaucoma filtration surgery. CONCLUSIONS: R667 inhibited TGF-β1-induced contraction and extracellular matrix synthesis in HTFs. Such effects might have contributed to the lowering of IOP by R667 in a rat model of glaucoma filtration surgery. RARγ agonists might thus prove effective for inhibition of scar formation after such surgery.