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

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.

A comprehensive spatial-temporal transcriptomic analysis of differentiating nascent mouse lens epithelial and fiber cells

“…To further elaborate on processes both up-and down-stream of Mtor , we focused here on protein translation, mTOR signaling, autophagy, and mitophagy. Although mTOR signaling was shown to play multiple roles in lens epithelial cell proliferation and migration (Boswell et al, 2017; Qin et al, 2017; Zhang et al, 2016) and rapamycin was reported to induce age onset cataracts in mouse (Wilkinson et al, 2012), the molecular players in lens have not been clearly described, even in previous RNA-seq analyses (Hoang et al, 2014; Khan et al, 2015). Here, we found that mTOR signaling was enriched in genes expressed higher in lens fibers (Fig.…”

Syndecan-4 Modulates Cell Polarity and Migration by Influencing Centrosome Positioning and Intracellular Calcium Distribution

“…Specifically, syndecan-4 directly binds fibronectin to promote cell adhesions, thereby affecting cell migration, whereas the syndecan-4/PKCα/RhoA signaling axis promotes focal adhesion formation (Matthews et al, 2008;Yin et al, 2017). Furthermore, the downregulation of syndecan-4 was shown to suppress integrin-mediated cell adhesion by inhibiting FAK phosphorylation (Qin et al, 2017). Moreover, the cytoplasmic domain of syndecan-4 interacts directly with α-actinin (Greene et al, 2003), leading to associations with other adhesion molecules, such as vinculin and zyxin (Cavalheiro et al, 2017), as well as the actin cytoskeleton (Choi et al, 2008).…”

Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

“…However, previous studies have demonstrated that syndecans act as co-receptors for several mediators via their heparan sulfate GAGs and concentrate heparin-binding proteins on the cell surface [3,37,38]. The role of syndecan-4 has been considered to facilitate the binding of heparin-binding proteins to their original receptors, leading to the acceleration of signals [39]. Lu et al reported that the binding of TGF-β to heparan sulfate at the cell membrane helps bring TGF-β to close proximity to its signaling receptors, and increases the local concentration of TGF-β [40].…”