title: Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen.
abstract: OBJECTIVE
  Skin fibrosis in the TSK mouse, a model of skin fibrosis seen in systemic sclerosis (SSc), is caused by a large in-frame duplication in the Fbn1 gene, tsk-Fbn1. We investigated whether tsk-Fbn1 might cause dermal fibrosis by affecting Fbn1 and associated extracellular matrices. We also studied whether deposition of microfibril-associated glycoprotein 2 (MAGP-2), a protein that is associated with fibrillin 1, was altered in the skin of patients with SSc.
  
  
  METHODS
  An in vitro model of the TSK mouse was created by conditionally expressing tsk-Fbn1 in mouse embryonic fibroblasts (MEFs). Cell cultures were examined by immunofluorescence and Western and Northern blotting to determine the effect of tsk-Fbn1 on the structure, expression, and deposition of fibrillin 1 (Fbn-1), type I collagen, and MAGP-2. The skin of TSK mice and SSc patients was analyzed by immunohistochemistry for MAGP-2 expression.
  
  
  RESULTS
  Expression of tsk-Fbn1 in cultured MEF cells altered the morphology of Fbn-1 fibers and increased the deposition of type I collagen into the extracellular matrix (ECM) without concomitantly changing messenger RNA expression, secretion, or processing of type I procollagen. Moreover, MEF cells expressing tsk-Fbn1 showed increased MAGP-2 matrix. MAGP-2 was increased in the dermis of TSK mice. Fibrotic SSc skin also showed higher levels of MAGP-2 in the dermis than nonfibrotic SSc skin and normal skin.
  
  
  CONCLUSIONS
  Tsk-Fbn1 altered ECM organization and caused fibrosis by affecting the deposition of MAGP-2 or other Fbn-1-associated proteins. Alterations in microfibril structure or deposition might contribute to fibrosis in SSc.
authors.affiliation: Boston University School of Medicine, The Arthritis Center, Boston, Massachusetts 02118, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lemaire
authors.forename: Guiseppina
authors.initials: G
authors.lastname: Farina
authors.forename: Eugene
authors.initials: E
authors.lastname: Kissin
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Constantine
authors.initials: C
authors.lastname: Bona
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Korn
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D003285:Contractile Proteins / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D051379:Mice; D008817:Mice, Mutant Strains; D020894:Microfibrils / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015394:Molecular Structure; D009154:Mutation; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D054392:Adipokines
chemical_list: D024042:Collagen Type I; D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C016598:microfibrillar protein