Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Sci Rep. 2017 Jul 28;7(1):6801. doi: 10.1038/s41598-017-06924-3.
Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial dysfunction causes serious vision loss. The only therapy for corneal haziness due to corneal endothelial diseases, including FECD, is corneal transplantation using donor corneas, and no pharmaceutical treatment is available. We provide evidence that the expression levels of transforming growth factor-β (TGF-β) isoforms and TGF-β receptors are high in the corneal endothelium of patients with FECD. A cell model based on patients with FECD shows that TGF-β signaling induced a chronic overload of ECM proteins to the endoplasmic reticulum (ER), thereby enhancing the formation of unfolded protein and triggering the intrinsic apoptotic pathway through the unfolded protein response (UPR). We propose that inhibition of TGF-β signaling may represent a novel therapeutic target that suppresses cell loss as well as the accumulation of ECM in FECD.
Fuchs 内皮角膜营养不良（FECD）是一种缓慢进展的双侧角膜内皮疾病，其特征是细胞外基质（ECM）的积累和角膜内皮细胞（CECs）的丧失。角膜内皮通过调节水合作用来维持角膜透明度；因此，角膜内皮功能障碍会导致严重的视力丧失。角膜混浊的唯一治疗方法，包括 FECD，是使用供体角膜进行角膜移植，目前尚无药物治疗方法。我们提供的证据表明，FECD 患者的角膜内皮中转化生长因子-β（TGF-β）异构体和 TGF-β 受体的表达水平较高。基于 FECD 患者的细胞模型表明，TGF-β 信号诱导 ECM 蛋白向内质网（ER）的慢性过载，从而增强未折叠蛋白的形成，并通过未折叠蛋白反应（UPR）触发内在凋亡途径。我们提出，抑制 TGF-β 信号可能代表一种新的治疗靶点，既能抑制细胞丢失，又能抑制 FECD 中 ECM 的积累。
