Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs

Abstract

Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their differential response to external stimuli could explain the protean clinical manifestations of SSc while offering the opportunity of targeted drug development. Small, non-coding RNA sequences (miRNAs) have demonstrated complex interactions between vasculature, immune activation, and extracellular matrices. Distinct miRNA profiles were identified in SSc skin specimens and blood samples containing a wide variety of dysregulated miRNAs. Their target genes are mainly involved in profibrotic pathways, but new lines of evidence also confirm their participation in impaired angiogenesis and aberrant immune responses. Research approaches focusing on earlier stages of the disease and on differential miRNA expression in various tissues could bring novel insights into SSc pathogenesis and validate the clinical utility of miRNAs as biomarkers and therapeutic targets.

Keywords: epigenetic mechanisms; miRNAs; pathogenesis; systemic sclerosis.

Figure 1

Illustration of epigenetic mechanisms. This figure is a schematical representation of the epigenetic mechanisms that modulate gene expression: (1) Histone modifications refer to post-translational modifications of the histone proteins leading to conformational changes that make DNA more or less accessible to RNA polymerase II (RNA POL II); (2) DNA methylation is an enzyme-mediated process consisting of the addition of a methyl (CH3) group to the 5-carbon of the cytosine ring from a CpG site. Clusters of CpG sites form a CpG island. The methylation status of a CpG island located in the promotor region of a gene can either lead to gene silencing if highly methylated or active gene transcription if slightly methylated; (3) Non-coding RNAs (lncRNAs and miRNAs) are functional RNA fragments transcribed from the DNA by RNA Pol II but unable to be translated into proteins. LncRNAs possess diverse functions, such as the capacity of altering mRNA splicing or recruiting chromatin remodeling proteins and transcription factors. MiRNAs have the ability to bind post-transcriptionally to a complementary sequence from a target mRNA and induce gene silencing. Depending on the degree of homology they can either inhibit transcription or induce mRNA cleavage.

Figure 2

TGF-β1, the main regulator of fibrosis, plays a central role in SSc pathogenesis. SMAD and non-SMAD TGF-β signaling pathways lead to transcription of fibrosis-related genes responsible for fibroblast proliferation, myofibroblast differentiation, and extracellular matrix deposition. Upregulation (red squares) or downregulation (blue squares) of diverse miRNAs interfere with these mechanisms and promote tissue fibrosis. KLF4: Kruppel-like factor 4; MMP1: matrix metalloproteinase 1; sFRP-1: secreted frizzled-related protein-1; DKK-1: Dickkopf-1; LRP 5/6: lipoprotein receptor-related proteins (LRP) 5 and 6; COL1A1: collagen type 1 alpha 1 chain; COL3A1: collagen type 3 alpha 1 chain; TAB1: transforming growth factor beta activated protein kinase 1; TGFR1: transforming growth factor beta receptor 1; TGFR2: transforming growth factor beta receptor 2; Wnt: Wnt signaling pathway; alpha-SMA: alpha-smooth muscle actin; CTGF: connective tissue growth factor; TIMPs: tissue inhibitors of metalloproteinases; IL-13R alpha 1: interleukin-13 receptor alpha 1; IL-4R alpha: interleukin-4 receptor alpha; STAT6: signal transducer and activator of transcription 6.