Akiko Sugiyama1, Keishi Kanno2, Norihisa Nishimichi3, Shoichiro Ohta4, Junya Ono5, Simon J Conway6, Kenji Izuhara7, Yasuyuki Yokosaki3, Susumu Tazuma1. 1. Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. 2. Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. kkanno@hiroshima-u.ac.jp. 3. Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. 4. Division of Medical Biochemistry, Department of Laboratory Medicine, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan. 5. Central Institute, Shino-Test Corporation, 2-29-14, Oonodai Minami-ku, Sagamihara, Kanagawa, 252-0331, Japan. 6. Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. 7. Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan.
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.
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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