title: Targeting miR-155 to Treat Experimental Scleroderma.
abstract: Scleroderma is a refractory autoimmune skin fibrotic disorder. Alterations of microRNAs in lesional skin could be a new approach to treating the disease. Here, we found that expression of miR-155 was up regulated in lesional skin tissue from patients with either systemic or localized scleroderma, and correlated with fibrosis area. Then we demonstrated the potential of miR-155 as a therapeutic target in pre-clinical scleroderma models. MiR-155(-/-) mice were resistant to bleomycin induced skin fibrosis. Moreover, topical antagomiR-155 could effectively treat mice primed with subcutaneous bleomycin. In primary skin fibroblast, miR-155 silencing could inhibit collagen synthesis function, as well as signaling intensity of two pro-fibrotic pathways, Wnt/β-catenin and Akt, simultaneously. We further showed that miR-155 could regulate the two pathways via directly targeting casein kinase 1α (CK1α) and Src homology 2-containing inositol phosphatase-1 (SHIP-1), as previous reports. Mice with miR-155 knockout or topical antagomir-155 treatment showed inhibited Wnt/β-catenin and Akt signaling in skin upon bleomycin challenge. Together, our data suggest the potential of miR-155 silencing as a promising treatment for dermal fibrosis, especially in topical applications.
authors.affiliation: Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China.
authors.forename: Qingran
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Xijing Hospital, The Fourth Military Medical University, Department of Dermatology, Xi'an 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China.
authors.forename: Chunde
authors.initials: C
authors.lastname: Bao
authors.affiliation: Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Fu
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018390:Gene Targeting; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D001761:Bleomycin; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt
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