title: The involvement of collagen triple helix repeat containing 1 in muscular dystrophies.
abstract: Fibrosis is the main complication of muscular dystrophies. We identified collagen triple helix repeat containing 1 (Cthrc1) in skeletal and cardiac muscles of mice, representing Duchenne and congenital muscle dystrophies (DMD and CMD, respectively), and dysferlinopathy. In all of the mice, Cthrc1 was associated with high collagen type I levels; no Cthrc1 or collagen was observed in muscles of control mice. High levels of Cthrc1 were also observed in biopsy specimens from patients with DMD, in whom they were reversibly correlated with that of β-dystroglycan, whereas collagen type I levels were elevated in all patients with DMD. At the muscle sites where collagen and Cthrc1 were adjacent, collagen fibers appeared smaller, suggesting involvement of Cthrc1 in collagen turnover. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of the transforming growth factor-β signaling, reduced Cthrc1 levels in skeletal and cardiac muscles of mice, representing DMD, CMD, and dysferlinopathy. The myofibroblasts infiltrating the dystrophic muscles of the murine models of DMD, CMD, and dysferlinopathy were the source of Cthrc1. Transforming growth factor-β did not affect Cthrc1 levels in the mdx fibroblasts but decreased them in the control fibroblasts, in association with increased migration of mdx fibroblasts and dystrophic muscle invasion by myofibroblasts. To our knowledge, this is the first demonstration of Cthrc1 as a marker of the severity of the disease progression in the dystrophic muscles, and as a possible target for therapy.
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Spector
authors.forename: Yael
authors.initials: Y
authors.lastname: Zilberstein
authors.forename: Adi
authors.initials: A
authors.lastname: Lavy
authors.forename: Olga
authors.initials: O
authors.lastname: Genin
authors.forename: Hila
authors.initials: H
authors.lastname: Barzilai-Tutsch
authors.forename: Ana
authors.initials: A
authors.lastname: Bodanovsky
authors.forename: Orna
authors.initials: O
authors.lastname: Halevy
authors.forename: Mark
authors.initials: M
authors.lastname: Pines
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology
chemical_list: C502426:CTHRC1 protein, human; D024042:Collagen Type I; C530500:Cthrc1 protein, mouse; D016326:Extracellular Matrix Proteins