Abstract
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.
Highlights
Cataract remains the leading cause of vision loss worldwide, accounting for 11 million cases of blindness and 35 million cases of visual impairment every year.[1,2] Currently, phacoemulsification with intraocular lens (IOL) implantation is the most effective treatment for cataract
We found that 50 ng/ml basic FGF (bFGF) promoted lens epithelial cells (LECs) proliferation, as the group treated with bFGF for 48 h had significantly higher optical density (OD) values than that of the untreated group (1.257 ± 0.091 versus 0.863 ± 0.091, Po0.01)
We found that treatment with 50 ng/ml bFGF for 48 h significantly increased the levels of cyclin E1, cyclin D1, CDK6, CDK4, and CDK2, which could be suppressed by SDC-4 KD (Figures 1e–g)
Summary
Cataract remains the leading cause of vision loss worldwide, accounting for 11 million cases of blindness and 35 million cases of visual impairment every year.[1,2] Currently, phacoemulsification with intraocular lens (IOL) implantation is the most effective treatment for cataract. This procedure has many postoperative complications.[3,4] The most common complication after cataract surgery is postoperative capsular opacification, which includes anterior capsular opacification (ACO) and posterior capsular opacification (PCO). SDC-4 is a widespread component of focal adhesion, and focal adhesion formation is increased upon SDC-4 overexpression.[24,25] the role of SDC-4 in the proliferation, migration, and adhesion of LECs has not been fully elucidated
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