Decorin, an anti-fibrogenic and fibrolytic glycoprotein, reduces established trabecular meshwork scarring and intraocular pressure and protects retinal function in a rat model of glaucoma.

Abstract

Purpose: Chronically raised intraocular pressure (IOP) is a major risk factor for the development of Primary Open Angle Glaucoma (POAG). Reduced outflow of aqueous humour secondary to fibrosis in the Trabecular Meshwork (TM) elevates IOP causing Retinal Ganglion Cell (RGC) death and blindness. Currently, reduction of IOP is recognised as the only modifiable risk factor. Decorin, a naturally occurring proteoglycan has anti-fibrogenic and fibrolytic properties that suppress scar formation and reverse established scarring in the CNS. Acting as a direct antagonist of pro-fibrogenic Transforming Growth Factor beta (TGF-β), Decorin also causes scar dissolution by activating proteases that lyse collagen, fibronectin and laminin. Hence, we suggest that Decorin is an alternative treatment strategy for POAG that has the potential to prevent progressive visual loss, by reducing IOP through reducing resistance to AqH outflow through MMP-induced dissolution of TM fibrosis and protecting RGC from death.

Methods: Rats received bi-weekly intracameral injections of 5ng/μl TGF-β (to induce TM fibrosis and raise IOP) or PBS (controls) for 30d. TGF-β injections were stopped at 16d when TM fibrosis was established and IOP had become consistently raised and thereafter rats were injected intracamerally with 5mg/ml Decorin or PBS. IOP were measured throughout and eyes harvested at 30d for immunohistological analysis of laminin and fibronectin to assess levels of TM fibrosis and of MMP to assess fibrolysis. RGC function was assessed using Visual Evoked Potentials (VEP) and survival was quantified in retinal whole mounts using FluoroGold back-labelling.

Results: A significant increase in IOP was observed by 9d in the TGF-β group, which became significantly raised by 14d until 30d compared to PBS. This increase in IOP induced a 30% loss of RGC numbers compared to PBS and a significant decrease in retinal function. By 30d, Decorin injections reduced established TM fibrosis (p<0.05) by enhancing levels of active MMP, lowered the IOP to baseline levels and preserved RGC viability.

Conclusions: Decorin lowered IOP by reversing established TM fibrosis and protecting RGC function in this model. Thus, intracameral Decorin treatment has the potential to be developed into as an effective therapy for patients with established progressive POAG.

Keywords: 568 intraocular pressure • 735 trabecular meshwork • 508 electrophysiology: non-clinical