Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9

Abstract

Ocular hypertension (OHT) is a serious adverse effect of the widely prescribed glucocorticoid (GC) therapy and, if left undiagnosed, it can lead to glaucoma and complete blindness. Previously, we have shown that the small chemical chaperone, sodium-4-phenylbutyrate (PBA), rescues GC-induced OHT by reducing ocular endoplasmic reticulum (ER) stress. However, the exact mechanism of how PBA rescues GC-induced OHT is not completely understood. The trabecular meshwork (TM) is a filter-like specialized contractile tissue consisting of TM cells embedded within extracellular matrix (ECM) that controls intraocular pressure (IOP) by constantly regulating aqueous humor (AH) outflow. Induction of abnormal ECM deposition in TM is a hallmark of GC-induced OHT. Here, we investigated whether PBA reduces GC-induced OHT by degrading abnormal ECM deposition in TM using mouse model of GC-induced OHT, ex vivo cultured human TM tissues and primary human TM cells. We show that topical ocular eye drops of PBA (1%) significantly lowers elevated IOP in mouse model of GC-induced OHT. Importantly, PBA prevents synthesis and deposition of GC-induced ECM in TM. We report for the first time that PBA can degrade existing abnormal ECM in normal human TM cells/tissues by inducing matrix metalloproteinase (MMP)9 expression and activity. Furthermore, inhibition of MMPs activity by chemical-inhibitor (minocycline) abrogated PBA’s effect on ECM reduction and its associated ER stress. Our study indicates a non-chaperone activity of PBA via activation of MMP9 that degrades abnormal ECM accumulation in TM.

The Role of Metalloproteinases and Their Tissue Inhibitors on Ocular Diseases: Focusing on Potential Mechanisms

“…Sodium 4-phenylbutyrate, a salt of aromatic short-chain fatty acid, decreased IOP in mice with dexamethasone 21acetate-induced ocular hypertension; in addition, treatment downregulated the protein expression of collagen I and fibronectin in the trabecular meshwork tissue, enhancing the aqueous humor outflow. The treatment also prevented the dexamethasone-stimulated synthesis of ECM components and endoplasmic reticulum stress markers in primary human trabecular meshwork cells and upregulated the gene expression and activity of MMP-9 in the same model, indicating that sodium 4-phenylbutyrate was able to degrade abnormal extracellular matrix accumulation in glaucoma [216].…”

Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-β1: Relevance to Pseudoexfoliation Glaucoma

“…This annotated pathway clearly shows that ER stress is present and that the UPR is activated in our experiment ( Figure 11 ). This cellular model of XFG may support the development of novel therapeutic interventions targeting the UPR and ER stress [ 92 , 93 , 94 ].…”

Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?

“…Furthermore, 4-PBA has shown the ability to decrease ER stress and prevent disease phenotypes in murine glaucoma models [304]. Importantly, it has also been demonstrated to lower IOP by promoting ECM degradation through the activation of matrix metalloproteinase (MMP)-9 [305].…”