Institute of Human Anatomy and Embryology, University of Regensburg, Universitätsstr. 31, Regensburg D-93053, Germany.
Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany.
Matrix Biol. 2021 Mar;97:1-19. doi: 10.1016/j.matbio.2021.02.002. Epub 2021 Feb 11.
Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease.
原发性开角型青光眼是一种神经退行性疾病，其特征是视神经轴突变性，是全球视力丧失和失明的常见原因。几项随机多中心研究已经确定眼压是其发展的主要危险因素，这是由于房水在小梁网中的流出阻力增加所致。然而，原发性开角型青光眼中流出阻力增加的分子机制尚未完全确定。其中一个被提出的因素是促纤维化转化生长因子（TGF）-β2，它在原发性开角型青光眼患者的房水中含量更高。在这项研究中，我们阐明了小富含亮氨酸的蛋白聚糖decorin 在房水流出组织区域中的作用，它是 TGF-β 的已知拮抗剂。利用 decorin 缺陷小鼠，我们发现 decorin 调节了经典流出途径中的 TGF-β 信号，体内缺乏 decorin 会导致眼压升高。此外，Dcn 小鼠表现出明显的视神经轴突丢失和胶质层的形态变化，这是青光眼的典型特征。此外，我们还发现，可溶性 decorin 可减弱 TGF-β2 介导的典型下游靶基因（包括 CCN2/CTGF、FN 和 COL IV）的合成和表达。最后，我们发现 decorin 和 TGF-β 之间存在负反馈调节，原发性开角型青光眼患者的经典流出途径中 decorin 的表达显著下调。综上所述，我们的研究结果表明，decorin 在原发性开角型青光眼的发病机制中起重要作用，并为这种严重疾病的治疗提供了新的视角。
