Exploration of Novel Markers of Posterior Capsular Opacification

Abstract

Cataract, the leading cause of blindness worldwide, is defined as the clouding of the ocular lens. While cataract surgery is commonly performed by removing the lens and replacing it with an intraocular lens (IOL), it only temporarily cures cataract and actually causes a fibrotic condition called posterior capsular opacification (PCO). PCO, or secondary cataract, results from the migration and proliferation of lens capsule cells remaining post cataract surgery (PCS). While laser treatments can cure PCO, this incurs risks to vision. Thus, a comprehensive understanding of the signaling pathways leading to lens epithelial cell (LEC) fibrosis must be reached in order to prevent PCO. Previous research discovered that over‐activation of transforming growth factor beta (TGF‐β) signaling leads to increased fibrosis. The bone morphogenetic protein (BMP) signaling pathway is important for normal cell behavior and, in other cell types, controls fibrosis by inhibiting TGF‐β signaling. This work explores possible relationships between BMP and TGF‐β signaling during PCO pathogenesis. RNA sequencing and immunostaining revealed that many fibrotic markers are upregulated by 48 hours PCS including alpha smooth muscle actin (αSMA), collagen I, and lysyl oxidase, an extracellular matrix (ECM) protein that plays a role in the cross‐linking of collagen‐1. These upregulations occur concurrently with increases in phosphorylated SMAD3 (pSMAD3), a marker of the TGF‐β signaling pathway which is known to mediate LEC fibrosis. Additionally, a decrease in pSMAD1/5/8, major effectors of BMP signaling, was observed at the same time point consistent with the known requirement for BMP signaling in normal lens epithelial cell biology. Notably, the mRNA for Gremlin, a BMP antagonist, upregulates several hundred‐fold in LECs by 48 hours PCS, while Gremlin protein levels upregulate in lens cells sharply within six hours PCS and reach high levels at 48 hours PCS, providing a possible explanation for the attenuation of pSMAD1/5/8 observed. These data suggest that the upregulation of Gremlin PCS may be a critical factor in the downregulation of BMP signaling and the upregulation of TGF‐β signaling necessary for the fibrotic response leading to PCO.Support or Funding InformationThe National Eye Institute grant EY015279 as well as the University of Delaware Summer Scholars program funded this work.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.