title: Mice overexpressing integrin αv in fibroblasts exhibit dermal thinning of the skin.
abstract: BACKGROUND
  Integrins, especially αv integrin (ITGAV), are thought to play central roles in tissue fibrosis and the pathogenesis of scleroderma. So far, skin phenotype of tissue-specific transgenic mice of ITGAV have not been investigated.
  
  
  OBJECTIVE
  To investigate the role of ITGAV in the skin fibrosis, we engineered transgenic mice that overexpress ITGAV in the fibroblasts under the control of the COL1A2 enhancer promoter.
  
  
  METHODS
  Protein or RNA expression was evaluated by real-time PCR, immunohistochemistry, immunoblotting and immunoprecipitation.
  
  
  RESULTS
  Dermal thickness and Masson's trichrome staining were decreased in ITGAV transgenic (Tg) mice compared with wild-type (WT) mice. Protein and mRNA levels of COL1A2, COL3A1, CTGF and integrin β3 were down-regulated in the skin of Tg mice. In addition, the cell proliferation of cultured dermal fibroblasts obtained from Tg mice skin was decreased compared to those of WT mice. FAK phosphorylation was reduced in fibroblasts cultured from Tg mice skin in comparison to WT mice fibroblasts. Integrin β3 siRNA inhibited FAK phosphorylation levels, while FAK inhibitor reduced the expression of collagens and CTGF in mice dermal fibroblasts.
  
  
  CONCLUSIONS
  The down-regulation of collagen or CTGF by decreased integrin β3 and FAK phosphorylation may cause the dermal thinning in Tg mice. Lower CTGF may also result in reduced growth of Tg mice fibroblasts. Our hypothesis is that the balance between α and β chain of integrins positively or negatively control collagen expression and dermal thickness. This study gave a new insight in the treatment of tissue fibrosis and scleroderma by balancing integrin expression.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Zhongzhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan. Electronic address: mjin@kumamoto-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kudo
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Nakayama
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Honda
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Katsunari
authors.initials: K
authors.lastname: Makino
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Ikko
authors.initials: I
authors.lastname: Kajihara
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Makino
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, 143 Shimo-kasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D039482:Integrin alpha5 / Q000235:genetics* / Q000378:metabolism*; D039661:Integrin beta3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012867:Skin / Q000378:metabolism* / Q000473:pathology*
chemical_list: C526318:CCN2 protein, mouse; C000609875:COL3A1 protein, mouse; D024042:Collagen Type I; D024061:Collagen Type III; D039482:Integrin alpha5; D039661:Integrin beta3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055513:Connective Tissue Growth Factor; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
keywords: Integrin αv; MMP-1; Transgenic mice