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以视神经轴突退化为特征的神经退行性疾病，是全世界视力丧失和失明的常见原因。几项随机多中心研究已确定眼内压是其发展的主要危险因素，这是由小梁网内房水的流出阻力增加引起的。然而，POAG 中增加流出阻力的分子机制尚未完全确定。提议的参与者之一是促纤维化转化生长因子 (TGF)-β2，它在 POAG 患者的房水中含量较高。在这项研究中，我们阐明了核心蛋白聚糖（一种小的富含亮氨酸的蛋白聚糖和已知的 TGF-β 拮抗剂）在房水流出组织区域中的作用。利用缺乏核心蛋白聚糖的小鼠，在体内引起眼压升高。此外，Dcn ^-/-小鼠表现出视神经轴突的显着丧失和神经胶质层的形态变化，这是青光眼的典型特征。此外，使用人小梁网细胞，我们发现可溶性核心蛋白聚糖减弱了 TGF-β2 介导的典型下游靶基因的合成和表达，包括CCN2/CTGF、FN和COL IV. 最后，我们发现了核心蛋白聚糖和 TGF-β 的负相互调节，在原发性开角型青光眼患者的典型流出途径中核心蛋白聚糖显着下调。总的来说，我们的结果表明核心蛋白聚糖在原发性开角型青光眼的发病机制中起着重要作用，并为治疗这种严重疾病提供了新的视角。