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.