Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.
Int J Mol Sci. 2021 Sep 18;22(18):10095. doi: 10.3390/ijms221810095.
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.
眼高压（OHT）是广泛应用的糖皮质激素（GC）治疗的严重不良反应，如果不进行诊断，它可能导致青光眼和完全失明。此前，我们已经表明，小分子化学伴侣，4-苯基丁酸钠（PBA），通过减少眼部内质网（ER）应激来挽救 GC 诱导的 OHT。然而，PBA 挽救 GC 诱导的 OHT 的确切机制尚不完全清楚。小梁网（TM）是一种过滤样的特化收缩组织，由嵌入细胞外基质（ECM）中的 TM 细胞组成，通过不断调节房水（AH）流出来控制眼内压（IOP）。TM 中异常 ECM 沉积的诱导是 GC 诱导的 OHT 的标志。在这里，我们使用 GC 诱导的 OHT 的小鼠模型、离体培养的人 TM 组织和原代人 TM 细胞，研究了 PBA 是否通过降解 TM 中的异常 ECM 沉积来减轻 GC 诱导的 OHT。我们表明，PBA（1%）的眼部滴眼可显著降低 GC 诱导的 OHT 小鼠模型中的升高的 IOP。重要的是，PBA 可防止 GC 诱导的 ECM 在 TM 中的合成和沉积。我们首次报道 PBA 可以通过诱导基质金属蛋白酶（MMP）9 的表达和活性来降解正常 TM 细胞/组织中现有的异常 ECM。此外，通过化学抑制剂（米诺环素）抑制 MMPs 活性，可消除 PBA 对 ECM 减少及其相关 ER 应激的作用。我们的研究表明 PBA 通过激活 MMP9 具有非伴侣蛋白活性，可降解 TM 中异常 ECM 的积累。
