title: 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.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Katsunari
authors.initials: K
authors.lastname: Makino
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.forename: Ayaka
authors.initials: A
authors.lastname: Hirano
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamane
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Eto
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kusano
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Honda
authors.forename: Ikko
authors.initials: I
authors.lastname: Kajihara
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Makino
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sakai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Masuguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
mesh_terms: D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D024042:Collagen Type I; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human