Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction

Akiko Sugiyama, Keishi Kanno, Norihisa Nishimichi, Shoichiro Ohta, Junya Ono, Simon Conway, Kenji Izuhara, Yasuyuki Yokosaki, Susumu Tazuma

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 αvβ5 and αvβ3 integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-α5β1 antibody had no effect. Consistently, αv integrin-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. Conclusion: Periostin exerts potent profibrotic activity mediated by αv integrin, suggesting the periostin–αv integrin axis as a novel therapeutic target for hepatic fibrosis.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalJournal of Gastroenterology
DOIs
StateAccepted/In press - Apr 4 2016

Fingerprint

Hepatic Stellate Cells
Integrins
Fibrosis
Liver
Collagen
Thioacetamide
Carbon Tetrachloride
Wounds and Injuries
Gene Silencing
Liver Cirrhosis
Cell Movement
Smooth Muscle
Actins
Anti-Idiotypic Antibodies
Ligands
Cell Line
Antibodies
Proteins

Keywords

  • Cell adhesion receptor
  • Cell migration
  • Liver fibrogenesis
  • Matricellular protein
  • Myofibroblasts

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction. / Sugiyama, Akiko; Kanno, Keishi; Nishimichi, Norihisa; Ohta, Shoichiro; Ono, Junya; Conway, Simon; Izuhara, Kenji; Yokosaki, Yasuyuki; Tazuma, Susumu.

In: Journal of Gastroenterology, 04.04.2016, p. 1-14.

Research output: Contribution to journalArticle

Sugiyama, Akiko ; Kanno, Keishi ; Nishimichi, Norihisa ; Ohta, Shoichiro ; Ono, Junya ; Conway, Simon ; Izuhara, Kenji ; Yokosaki, Yasuyuki ; Tazuma, Susumu. / Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction. In: Journal of Gastroenterology. 2016 ; pp. 1-14.
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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 αvβ5 and αvβ3 integrins suppressed cell attachment to periostin by 60 and 30 {\%} respectively, whereas anti-α5β1 antibody had no effect. Consistently, αv integrin-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. Conclusion: Periostin exerts potent profibrotic activity mediated by αv integrin, suggesting the periostin–αv integrin axis as a novel therapeutic target for hepatic fibrosis.",
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T1 - Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction

AU - Sugiyama, Akiko

AU - Kanno, Keishi

AU - Nishimichi, Norihisa

AU - Ohta, Shoichiro

AU - Ono, Junya

AU - Conway, Simon

AU - Izuhara, Kenji

AU - Yokosaki, Yasuyuki

AU - Tazuma, Susumu

PY - 2016/4/4

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N2 - 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 αvβ5 and αvβ3 integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-α5β1 antibody had no effect. Consistently, αv integrin-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. Conclusion: Periostin exerts potent profibrotic activity mediated by αv integrin, suggesting the periostin–αv integrin axis as a novel therapeutic target for hepatic fibrosis.

AB - 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 αvβ5 and αvβ3 integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-α5β1 antibody had no effect. Consistently, αv integrin-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. Conclusion: Periostin exerts potent profibrotic activity mediated by αv integrin, suggesting the periostin–αv integrin axis as a novel therapeutic target for hepatic fibrosis.

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KW - Cell migration

KW - Liver fibrogenesis

KW - Matricellular protein

KW - Myofibroblasts

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