title: Increased expression of type I collagen induced by microfibril-associated glycoprotein 2: novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma.
abstract: OBJECTIVE
  Mutations in fibrillin 1, a key component of extracellular microfibrils, are associated with connective tissue disorders such as Marfan's syndrome or skin fibrosis in the tight skin mouse model of scleroderma. Previous studies have suggested that fibrillin 1 mediates skin fibrosis via its interface with associated microfibrillar proteins and type I collagen; in particular, microfibril-associated glycoprotein 2 (MAGP-2), an extracellular matrix protein that binds to fibrillins and the alphavbeta3 integrin, is increased in TSK mouse and human scleroderma skin. Because the function of MAGP-2 in the biologic processes of the matrix remains unknown, this study investigated whether MAGP-2 regulates type I collagen.
  
  
  METHODS
  Fibroblast cultures conditionally overexpressing MAGP-2 were developed. Cells were analyzed by Western blotting, Northern blotting, pulse-chase analysis, and immunofluorescence to assess the effect of MAGP-2 on type I collagen.
  
  
  RESULTS
  Cells overexpressing MAGP-2 formed increased MAGP-2 matrix and showed a 3-fold increase in intracellular type I procollagen. This increase was associated with increased levels of type I collagen in the medium and matrix. Increased type I collagen colocalized with the MAGP-2 matrix. MAGP-2 overexpression had no effect on type I procollagen messenger RNA, but markedly increased the half-life of type I procollagen. MAGP-2 induced type I collagen even under conditions in which no MAGP-2 matrix was detectable, and did not require the presence of the RGD motif of MAGP-2 in its integrin-binding site.
  
  
  CONCLUSIONS
  This study shows that MAGP-2 stabilizes type I procollagen, identifying an important function of MAGP-2 in extracellular matrix homeostasis. It also suggests that MAGP-2 might mediate skin fibrosis in TSK mice and in patients with scleroderma.
authors.affiliation: The Arthritis Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. rlemaire@arthritis.bu.edu
authors.forename: Raphael
authors.initials: R
authors.lastname: Lemaire
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Korn
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis*; D003285:Contractile Proteins / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts; D005355:Fibrosis; D051379:Mice; D020894:Microfibrils / Q000473:pathology; D000072260:RNA Splicing Factors; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000503:physiopathology*; D012867:Skin / Q000473:pathology*
chemical_list: D024042:Collagen Type I; D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000072260:RNA Splicing Factors; C016598:microfibrillar protein