Tissue Transglutaminase Mediated Ocular Hypertension and Effects of a Small Molecule Crosslinking Modulator

Purpose: Transforming Growth Factor-β2 (TGF-β2) induces expression of the crosslinking enzyme tissue transglutaminase (TGM2) in human trabecular meshwork (TM) cells. We studied (1) whether TGM2 overexpression in the TM can increase intraocular pressure (IOP) and decrease aqueous humor (AH) outflow facility (C) in mice and (2) whether a small molecule TGM2 inhibitor can decrease ECM crosslinking in-vitro. Methods: 2μl of the expression vector Ad5.CMV.TGM2 (1-50 × 106 pfu) was injected intravitreally (OS) in BALBc/J (n=18) or C57BL/6J mice (n=9), while contralateral eyes served as uninjected controls. Daytime conscious IOPs were measured (Tonolab) twice/week. C was measured following IOP elevation in BALBc/J (n=6) and C57BL/6J (n=3) mice. In vitro, primary human glaucoma TM cells (GTM 125, GTM 60 A and GTM 46) were treated with a small molecule TGM2 inhibitor (5nM). Results: Ad5.CMV.TGM2 injection significantly elevated IOP, where BALBc/J showed maximum IOP at Day 19, [15.86 mmHg (injected) vs. 10.7 mmHg (control), (p Conclusions: TGM2 overexpression in the mouse TM significantly elevates IOP and decreases the AH outflow facility. A TGM2 inhibitor decreased crosslinking in TM primary cells. In future, we will study the role of TGM2 and the TGM2 small molecule inhibitor in TGFβ2 induced ocular hypertension.