Sugiyama Akiko, Kanno Keishi, Nishimichi Norihisa, Ohta Shoichiro, Ono Junya, Conway Simon J, Izuhara Kenji, Yokosaki Yasuyuki, Tazuma Susumu
Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
J Gastroenterol. 2016 Dec;51(12):1161-1174. doi: 10.1007/s00535-016-1206-0. Epub 2016 Apr 4.
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) 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 α-smooth muscle actin and collagen, indicating a profibrotic property. An antibody targeting αβ and αβ integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-αβ antibody had no effect. Consistently, α 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.
Periostin exerts potent profibrotic activity mediated by α integrin, suggesting the periostin-α integrin axis as a novel therapeutic target for hepatic fibrosis.
骨膜蛋白是一种基质细胞蛋白，作为整合素的配体，是组织重塑和纤维化所必需的。我们研究了骨膜蛋白在肝纤维化中的作用及其相关机制。
使用原代肝星状细胞（HSCs）和永生化HSC细胞系LX2来研究骨膜蛋白的促纤维化特性以及骨膜蛋白与整合素的相互作用。野生型和骨膜蛋白缺陷（periostin-/-）小鼠分别接受由肝毒性（四氯化碳或硫代乙酰胺）或胆汁淤积性（3,5-二乙氧羰基-1,4-二氢可力丁）损伤诱导的两种不同肝纤维化模型。
HSCs和LX2细胞中骨膜蛋白的表达随着它们的激活而增加。骨膜蛋白的基因沉默导致促纤维化标志物水平显著降低。除了对骨膜蛋白反应增强的细胞迁移外，在骨膜蛋白上培养的LX2细胞显示出α-平滑肌肌动蛋白和胶原蛋白的显著诱导，表明具有促纤维化特性。靶向αβ1和αβ3整合素的抗体分别抑制细胞与骨膜蛋白的附着60%和30%，而抗αβ5抗体则无作用。一致地，α1整合素沉默的LX2细胞表现出与骨膜蛋白的附着减少，促纤维化标志物水平显著降低。此外，在小鼠模型中观察到了骨膜蛋白的这些促纤维化作用。与野生型小鼠中广泛的胶原沉积相反，periostin-/-小鼠由肝毒性和胆汁淤积性肝损伤诱导的肝纤维化不太明显。因此，periostin-/-小鼠中的促纤维化标志物显著降低。
骨膜蛋白通过α1整合素发挥强大的促纤维化活性，提示骨膜蛋白-α1整合素轴作为肝纤维化的新型治疗靶点。
