title: Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αvintegrin interaction.
abstract: BACKGROUND
  Periostin is a matricellular protein that serves as a ligand for integrins and is required for tissue remodeling and fibrosis. We investigated the role of periostin in hepatic fibrosis and the mechanisms involved.
  
  
  METHODS
  Primary hepatic stellate cells (HSCs) and the HSC-immortalized cell line LX2 were used to study the profibrotic property of periostin and the interaction of periostin with integrins. Wild-type and periostin-deficient (periostin-/-) mice were subjected to two distinct models of liver fibrosis induced by hepatotoxic (carbon tetrachloride or thioacetamide) or cholestatic (3.5-diethoxycarbonyl-1.4-dihydrocollidine) injury.
  
  
  RESULTS
  Periostin expression in HSCs and LX2 cells increased in association with their activation. Gene silencing of periostin resulted in a significant reduction in the levels of profibrotic markers. In addition to enhanced cell migration in response to periostin, LX2 cells incubated on periostin showed significant induction of α-smooth muscle actin and collagen, indicating a profibrotic property. An antibody targeting αvβ5and αvβ3integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-α5β1antibody had no effect. Consistently, αvintegrin-silenced LX2 cells exhibited decreased attachment to periostin, with a significant reduction in the levels of profibrotic markers. Moreover, these profibrotic effects of periostin were observed in the mouse models. In contrast to extensive collagen deposition in wild-type mice, periostin-/-mice developed less noticeable hepatic fibrosis induced by hepatotoxic and cholestatic liver injury. Accordingly, the profibrotic markers were significantly reduced in periostin-/-mice.
  
  
  CONCLUSIONS
  Periostin exerts potent profibrotic activity mediated by αvintegrin, suggesting the periostin-αvintegrin axis as a novel therapeutic target for hepatic fibrosis.
authors.affiliation: Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sugiyama
authors.affiliation: Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. kkanno@hiroshima-u.ac.jp.
authors.forename: Keishi
authors.initials: K
authors.lastname: Kanno
authors.affiliation: Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Nishimichi
authors.affiliation: Division of Medical Biochemistry, Department of Laboratory Medicine, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Central Institute, Shino-Test Corporation, 2-29-14, Oonodai Minami-ku, Sagamihara, Kanagawa, 252-0331, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Ono
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
authors.affiliation: Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Yokosaki
authors.affiliation: Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tazuma
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000502:physiology*; D039564:Integrin alphaV / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018345:Mice, Knockout; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology
chemical_list: D015815:Cell Adhesion Molecules; D039564:Integrin alphaV; C082838:Postn protein, mouse
keywords: Cell adhesion receptor; Cell migration; Liver fibrogenesis; Matricellular protein; Myofibroblasts