Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via alpha sub(v) integrin interaction

• Published in: Journal of gastroenterology 2016-12, Vol.51 (12), p.1161-1174
• Main Authors: Sugiyama, Akiko, Kanno, Keishi, Nishimichi, Norihisa, Ohta, Shoichiro, Ono, Junya, Conway, Simon J, Izuhara, Kenji, Yokosaki, Yasuyuki, Tazuma, Susumu
• Format: Article
• Language: English
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-016-1206-0

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. 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 super(-/-)) 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. 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 alpha -smooth muscle actin and collagen, indicating a profibrotic property. An antibody targeting alpha sub(v) beta sub(5) and alpha sub(v) beta sub(3) integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti- alpha sub(5) beta sub(1) antibody had no effect. Consistently, alpha sub(v) 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 super(-/-) mice developed less noticeable hepatic fibrosis induced by hepatotoxic and cholestatic liver injury. Accordingly, the profibrotic markers were significantly reduced in periostin super(-/-) mice. Periostin exerts potent profibrotic activity mediated by alpha sub(v) integrin, suggesting the periostin- alpha sub(v) integrin axis as a novel therapeutic target for hepatic fibrosis.