Journal of gastroenterology · 2016
Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction.
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Sugiyama Akiko, Kanno Keishi, Nishimichi Norihisa, Ohta Shoichiro, Ono Junya, Conway Simon J, Izuhara Kenji, Yokosaki Yasuyuki, Tazuma Susumu
Аннотация
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.
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.