title: In Crohn's disease fibrosis-reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts.
abstract: Intestinal fibrosis with stricture formation is a complication of CD (Crohn's disease) that may mandate surgical resection. Accurate biomarkers that reflect the relative contribution of fibrosis to an individual stricture are an unmet need in managing patients with CD. The miRNA-29 (miR-29) family has been implicated in cardiac, hepatic and pulmonary fibrosis. In the present study, we investigated the expression of miR-29a, miR-29b and miR-29c in mucosa overlying a stricture in CD patients (SCD) paired with mucosa from non-strictured areas (NSCD). There was significant down-regulation of the miR-29 family in mucosa overlying SCD compared with mucosa overlying NSCD. miR-29b showed the largest fold-decrease and was selected for functional analysis. Overexpression of miR-29b in CD fibroblasts led to a down-regulation of collagen I and III transcripts and collagen III protein, but did not alter MMP (matrix metalloproteinase)-3, MMP-12 and TIMP (tissue inhibitor of metalloproteinase)-1 production. TGF (transforming growth factor)-β1 up-regulated collagen I and III transcripts and collagen III protein as a consequence of the down-regulation of miR-29b, and TGF-β1-induced collagen expression was reversed by exogenous overexpression of miR-29b. Furthermore, serum levels of miR-29 were lower in patients with stricturing disease compared with those without. These findings implicate the miR-29 family in the pathogenesis of intestinal fibrosis in CD and provide impetus for the further evaluation of the miR-29 family as biomarkers.
authors.affiliation: *Centre for Digestive Diseases and National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Anke
authors.initials: A
authors.lastname: Nijhuis
authors.affiliation: †Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Paolo
authors.initials: P
authors.lastname: Biancheri
authors.affiliation: *Centre for Digestive Diseases and National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Amy
authors.initials: A
authors.lastname: Lewis
authors.affiliation: ‡Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Cleo L
authors.initials: CL
authors.lastname: Bishop
authors.affiliation: †Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giuffrida
authors.affiliation: §Academic Surgery Unit, Royal London Hospital, London, U.K.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chan
authors.affiliation: ¶Department of Cellular Pathology, Royal London Hospital, London, U.K.
authors.forename: Roger
authors.initials: R
authors.lastname: Feakins
authors.affiliation: *Centre for Digestive Diseases and National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.affiliation: ∥Department of Internal Medicine, S. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sabatino
authors.affiliation: ∥Department of Internal Medicine, S. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Gino Roberto
authors.initials: GR
authors.lastname: Corazza
authors.affiliation: †Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: MacDonald
authors.affiliation: *Centre for Digestive Diseases and National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: James O
authors.initials: JO
authors.lastname: Lindsay
authors.affiliation: *Centre for Digestive Diseases and National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, U.K.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Silver
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D024061:Collagen Type III / Q000096:biosynthesis* / Q000235:genetics; D003251:Constriction, Pathologic / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation; D005355:Fibrosis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1