Killing two birds with one stone: dual blockade of integrin and FGF signaling through targeting syndecan-4 in postoperative capsular opacification

• Published in: Cell death & disease Vol. 8; no. 7; p. e2920
• Main Authors: Qin, Yingyan, Zhu, Yi, Luo, Furong, Chen, Chuan, Chen, Xiaoyun, Wu, Mingxing
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 13.07.2017; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Age; AKT protein; Animals; Anterior Chamber - metabolism; Anterior Chamber - pathology; Capsule Opacification - metabolism; Capsule Opacification - pathology; Capsule Opacification - surgery; Cataracts; Cell activation; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell growth; Cell Line; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Disease Models, Animal; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Extracellular matrix; Extracellular signal-regulated kinase; Eye surgery; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factors; Focal adhesion kinase; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Integrins - metabolism; Kinases; Lens, Crystalline - cytology; Mice; Mice, Knockout; Original; Phosphorylation; Postoperative period; Protein Kinases - metabolism; Retina - metabolism; Retina - pathology; RNA Interference; Signal transduction; Signal Transduction - drug effects; Surgery; Syndecan; Syndecan-4 - antagonists & inhibitors; Syndecan-4 - genetics; Syndecan-4 - metabolism; TOR protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.315

The most common complication after cataract surgery is postoperative capsular opacification, which includes anterior capsular opacification (ACO) and posterior capsular opacification (PCO). Increased adhesion of lens epithelial cells (LECs) to the intraocular lens material surface promotes ACO formation, whereas proliferation and migration of LECs to the posterior capsule lead to the development of PCO. Cell adhesion is mainly mediated by the binding of integrin to extracellular matrix proteins, while cell proliferation and migration are regulated by fibroblast growth factor (FGF). Syndecan-4 (SDC-4) is a co-receptor for both integrin and FGF signaling pathways. Therefore, SDC-4 may be an ideal therapeutic target for the prevention and treatment of postoperative capsular opacification. However, how SDC-4 contributes to FGF-mediated proliferation, migration, and integrin-mediated adhesion of LECs is unclear. Here, we found that downregulation of SDC-4 inhibited FGF signaling through the blockade of ERK1/2 and PI3K/Akt/mTOR activation, thus suppressing cell proliferation and migration. In addition, downregulation of SDC-4 suppressed integrin-mediated cell adhesion through inhibiting focal adhesion kinase (FAK) phosphorylation. Moreover, SDC-4 knockout mice exhibited normal lens morphology, but had significantly reduced capsular opacification after injury. Finally, SDC-4 expression level was increased in the anterior capsule LECs of age-related cataract patients. Taken together, we for the first time characterized the key regulatory role of SDC-4 in FGF and integrin signaling in human LECs, and provided the basis for future pharmacological interventions of capsular opacification.