The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

Abstract

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3′-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.

The role of genetics and epigenetics in the pathogenesis of systemic sclerosis

“…Down regulation of let7a contributes to the accumulation of type I collagen in fibroblasts in the context of SSc, and the intermittent overexpression of let7a in the skin by intraperitoneal miRNA injection improved skin fibrosis induced by bleomycin in mice. 80 In fibroblasts from healthy donors, miR196a func tions to inhibit the production of type I collagen 72 and its expression is under the control of the discoidin domain receptor 2 (DDR2). 81 However, in fibroblasts from patients with SSc, the increased production of TGFβ directly inhibits the expression of both miR196a and DDR2, thereby impairing the miR196amediated nega tive feedback that controls type I collagen production and tissue fibrosis.…”

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

“…Several "omics" studies, using approaches such as genomics (Katsuma et al, 2001;Zuo et al, 2002;Kaminski, 2003) and proteomics (Kypreou et al, 2008;Kim et al, 2010), have been performed so far using BLM animal models. Furthermore, some studies that comprehensively analyzed micro RNA (miRNA) regulatory networks in pulmonary fibrosis have recently gained much attention (Liu et al, 2010;Xie et al, 2011;Xiao et al, 2012;Honeyman et al, 2013;Makino et al, 2013).…”

Hair miR‐29a levels are decreased in patients with scleroderma

“…Increased evidence has shown that serum miRNA levels can be biomarkers for various human diseases. Previously, for example, we demonstrated that serum let-7a levels were significantly decreased in SSc patients than in control subjects, inversely correlating with the severity of skin sclerosis (5). On the other hand, we also measured serum levels of miR-29a in SSc patients, but found that there was no significant difference in the serum miR29a levels between control subjects and SSc patients (6).…”