Molecular and Histopathological Changes Associated with Keratoconus

Abstract

Keratoconus (KC) is a corneal thinning disorder that leads to loss of visual acuity through ectasia, opacity, and irregular astigmatism. It is one of the leading indicators for corneal transplantation in the Western countries. KC usually starts at puberty and progresses until the third or fourth decade; however its progression differs among patients. In the keratoconic cornea, all layers except the endothelium have been shown to have histopathological structural changes. Despite numerous studies in the last several decades, the mechanisms of KC development and progression remain unclear. Both genetic and environmental factors may contribute to the pathogenesis of KC. Many previous articles have reviewed the genetic aspects of KC, but in this review we summarize the histopathological features of different layers of cornea and discuss the differentially expressed proteins in the KC-affected cornea. This summary will help emphasize the major molecular defects in KC and identify additional research areas related to KC, potentially opening up possibilities for novel methods of KC prevention and therapeutic intervention.

Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-affected Corneas

“…Another factor that can influence the impact of oxidative stress is disruption of iron homeostasis, which can lead to various corneal diseases including KC 20,21,43,44 . Fleisher ring, a ring of iron deposition in the corneal cone, is a typical clinical sign for KC 45 . Importantly, TFRC, a cellular receptor for iron-ferritin complex uptake 46 , has been identified to have elevated expression in KC cornea with both RNA-Seq and ddPCR in our study.…”

“…Dry eye symptoms have been reported in KC patients [68][69][70] , thus reduced expression of AQP5 might account for dry eye symptoms in some KC patients. Extracellular matrix (ECM) regulatory pathways are important for corneal integrity; however dysregulation in these pathways have been reported with KC progression 24,45 . Previous studies have shown an up-regulation of ECM degradative enzymes (such as matrix metalloproteinases and cathepsin) and/or down-regulation of their inhibitors (such as α1-protease inhibitor, α2-macroglobulin, secretory Leukocyte Peptidase Inhibitor, and TIMPs) 32,39,71 .…”

Pathogenesis of Keratoconus: The intriguing therapeutic potential of Prolactin-inducible protein

“…In addition to evidence from tear proteomics, tissue studies have highlighted biochemical abnormalities in KC, with reports of decreased, increased, or even normal levels of proteoglycans (Critchfield et al, 1988; Garcia et al, 2016; Khaled et al, 2017; Sawaguchi et al, 1994). These studies indicate a possible disruption in the molecular mechanisms regulating ECM homeostasis.…”

“…The different distribution of stromal lamellae in KC compared to normal corneas has been suggested as a precursor for corneal thinning and KC development (Khaled et al, 2017). …”

“…Various studies have reported that, during the gestational period, women have experienced a significant progression in KC, as indicated by reversible fluctuations in corneal topography and a decrease in corrected distance visual acuity (Hoogewoud et al, 2013; Pizzarello, 2003). This has led to the suggestion that pregnancy may be considered a risk factor for KC (Bilgihan et al, 2011; Khaled et al, 2017), and has implicated the role of hormone changes. Furthermore, hormonal alterations that occur during pregnancy have a negative impact on corneal biomechanics.…”