title: Targeting miR-21 to treat psoriasis.
abstract: Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.
authors.affiliation: F-BBVA-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.forename: María
authors.initials: M
authors.lastname: Jiménez
authors.forename: Helia B
authors.initials: HB
authors.lastname: Schonthaler
authors.forename: Raquel
authors.initials: R
authors.lastname: Navarro
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Delgado
authors.forename: María José
authors.initials: MJ
authors.lastname: Concha-Garzón
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.forename: Susanna
authors.initials: S
authors.lastname: Obad
authors.forename: Esteban
authors.initials: E
authors.lastname: Daudén
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage*; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D016038:Skin Transplantation; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D018808:Transcription Factor AP-1; C577686:interleukin-6, mouse; C477371:locked nucleic acid; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse