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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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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Abbreviations

Col1α1:

Collagen type I, alpha 1

DDC:

3,5-Diethoxycarbonyl-1,4-dihydrocollidine

DMEM:

Dulbecco’s modified Eagle’s medium

ECM:

Extracellular matrix

FBS:

Fetal bovine serum

HSC:

Hepatic stellate cell

siRNA:

Small interfering RNA

α-SMA:

α-Smooth muscle actin

TAA:

Thioacetamide

TGF:

Transforming growth factor

TIMP-1:

Tissue inhibitor of metalloproteinase 1

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Acknowledgments

Part of this study was presented at 114th Annual Meeting and the 116th Annual Meeting of the American Gastroenterological Association. This work was supported by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan to Susumu Tazuma and in part by the Japan Society for the Promotion of Science KAKENHI grants Scientific Research (B) 26293174 and Challenging Exploratory Research 24659367 to Yasuyuki Yokosaki. Experiments were conducted in part at the Analysis Center of Life Science, Hiroshima University.

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Authors and Affiliations

  1. Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Akiko Sugiyama, Keishi Kanno & Susumu Tazuma

  2. Cell–Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Norihisa Nishimichi & Yasuyuki Yokosaki

  3. Division of Medical Biochemistry, Department of Laboratory Medicine, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan

    Shoichiro Ohta

  4. Central Institute, Shino-Test Corporation, 2-29-14, Oonodai Minami-ku, Sagamihara, Kanagawa, 252-0331, Japan

    Junya Ono

  5. Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    Simon J. Conway

  6. Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan

    Kenji Izuhara

Authors
  1. Akiko Sugiyama
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Corresponding author

Correspondence to Keishi Kanno.

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Conflict of interest

Kenji Izuhara received a research grant from Chugai Pharmaceutical Co. Ltd and unrestricted grant from Shino-test Co. Ltd, and serves as a consultant to Chugai Pharmaceutical Co. Ltd. and AQUA Therapeutics Co. Ltd.

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Sugiyama, A., Kanno, K., Nishimichi, N. et al. Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction. J Gastroenterol 51, 1161–1174 (2016). https://doi.org/10.1007/s00535-016-1206-0

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  • DOI: https://doi.org/10.1007/s00535-016-1206-0

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