Sodium 4-phenylbyrate rescues glucocorticoid-induced ocular hypertension by reducing abnormal ECM deposition in the TM via activation of MMP9

Purpose: Ocular hypertension (OHT) is a serious side effect of glucocorticoid (GC) therapy and if left undiagnosed, it leads to glaucoma. Previously, we have shown that, sodium-4-phenylbutyrate (PBA) rescues GC-induced OHT. However, the exact mechanism behind PBA mediated reduction of GC-induced OHT is not completely understood. Here, we examined whether PBA rescues GC-induced OHT by reducing abnormal ECM deposition via activating MMP. Methods: GC-induced OHT mice were topically instilled 1% PBA or vehicle twice daily. IOPs and outflow facility were analyzed. Immunostaining, western blot and qPCR were performed to analyze the effect of PBA on GC-induced ECM deposition and ER stress in primary human TM cells, mouse and ex-vivo cultured human TM tissues. Effect of PBA on MMP's activity was analyzed by zymography. Results: Topical PBA eye-drops reduced GC-induced OHT and improved outflow facility significantly. PBA reduced GC-induced intracellular and extracellular ECM accumulation, and prevented induction of ER stress in primary human TM cells, ex-vivo human cultured TM tissues and mouse TM tissues. We observed that PBA can reduce existing ECM deposition when primary TM cells were grown on decellularized GC-treated ECM. Gene expression, western blot and zymography assays revealed that PBA induces increased expression and activity of MMP-9. Inhibition of MMP-9 activity by chemical-inhibitors abrogated PBA's effect on ECM reduction. Conclusions: PBA can be a very attractive treatment for general POAG via targeting abnormal ECM accumulation in the TM.