Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)β(3) engagement and PI3K/pAkt/NFκB signaling.
Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)β(3) engagement and PI3K/pAkt/NFκB signaling.
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DOI：
10.1002/hep.24701
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发表时间：
2012-02
期刊：
影响因子：
13.5
通讯作者：
Nieto, Natalia
中科院分区：
文献类型：
--
作者：
Urtasun, Raquel;Lopategi, Aritz;George, Joseph;Leung, Tung-Ming;Lu, Yongke;Wang, Xiaodong;Ge, Xiaodong;Fiel, Maria Isabel;Nieto, Natalia
肝纤维化发病机制中的一个关键特征是纤维状胶原-I沉积;然而，可能成为关键治疗靶点的介质仍然难以捉摸。我们假设，骨桥蛋白（OPN），细胞外基质（ECM）细胞因子表达的肝星状细胞（HSC），可以驱动纤维化通过调节HSC促纤维化表型和胶原-I的表达。rOPN以TGFβ非依赖性方式上调原代HSC中的胶原蛋白-I，而下调基质金属蛋白酶-13（MMP 13），因此有利于瘢痕形成。rOPN激活原代HSC -通过增加α-平滑肌肌动蛋白（α-SMA）表达证实-并增强其侵袭和伤口愈合潜力。从野生型（WT）小鼠分离的HSC比从Opn-/-小鼠分离的HSC更促纤维化，并且用Ad-OPN感染原代HSC增加胶原-I，表明两种蛋白质之间的相关性。OPN通过整合素αvβ3的结合和PI 3 K-pAkt-NFκB信号通路的激活诱导I型胶原的形成，而CD 44结合和mTOR-p70 S6 K不参与OPN的诱导。整合素αvβ3的中和作用阻止了OPN介导的PI 3 K-pAkt-NFκB信号级联的激活和I型胶原的上调。同样地，抑制PI 3 K和NFκB可阻断OPN介导的I型胶原增加。与健康个体相比，丙型肝炎肝硬化患者显示I型胶原和切割的OPN共同诱导。四氯化碳（CCl 4）注射或硫代乙酰胺（TAA）治疗引起的急性和慢性肝损伤均升高OPN表达。活性氧在体外和体内上调OPN，抗氧化剂阻止了这种作用。与WT小鼠相比，OpnHEP Tg小鼠出现自发性肝纤维化。最后，慢性CCl 4注射和TAA治疗导致WT比Opn-/-小鼠更多的肝纤维化，而OpnHEP Tg小鼠则相反。OPN作为ECM蛋白网络内的细胞因子出现，驱动胶原蛋白-I的增加，从而导致瘢痕形成和肝纤维化。
A key feature in the pathogenesis of liver fibrosis is fibrillar collagen-I deposition; yet, mediators that could be key therapeutic targets remain elusive. We hypothesized that osteopontin (OPN), an extracellular matrix (ECM) cytokine expressed in hepatic stellate cells (HSC), could drive fibrogenesis by modulating the HSC profibrogenic phenotype and collagen-I expression. rOPN up-regulated collagen-I protein in primary HSC in a TGFβ-independent fashion whereas it down-regulated matrix metalloprotease-13 (MMP13) thus favoring scarring. rOPN activated primary HSC -confirmed by increased α-smooth muscle actin (α-SMA) expression- and enhanced their invasive and wound-healing potential. HSC isolated from wild type (WT) mice were more profibrogenic than those from Opn-/- mice and infection of primary HSC with an Ad-OPN increased collagen-I, indicating correlation between both proteins. The OPN induction of collagen-I occurred via integrin αvβ3 engagement and activation of the PI3K-pAkt-NFκB signaling pathway, while CD44-binding and mTOR-p70S6K were not involved. Neutralization of integrin αvβ3 prevented the OPN-mediated activation of the PI3K-pAkt-NFκB signaling cascade and collagen-I up-regulation. Likewise, inhibition of PI3K and NFκB blocked the OPN-mediated collagen-I increase. HCV-cirrhotic patients showed co-induction of collagen-I and cleaved OPN compared to healthy individuals. Acute and chronic liver injury by carbon tetrachloride (CCl4)-injection or thioacetamide (TAA)-treatment elevated OPN expression. Reactive oxygen species up-regulated OPN in vitro and in vivo and antioxidants prevented this effect. OpnHEP Tg mice developed spontaneous liver fibrosis compared to WT mice. Lastly, chronic CCl4-injection and TAA-treatment caused more liver fibrosis to WT than to Opn-/- mice and the reverse occurred in OpnHEP Tg mice. OPN emerges as a cytokine within the ECM protein network driving the increase in collagen-I protein contributing to scarring and liver fibrosis.
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影响因子：
13.5
作者：
García-Trevijano, ER;Iraburu, MJ;Rojkind, M
通讯作者：
Rojkind, M
影响因子：
5.6
作者：
Büttner, C;Skupin, A;Rieber, EP
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影响因子：
6
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
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影响因子：
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作者：
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Desmoulière, A
影响因子：
13.5
作者：
Nieto, Natalia
通讯作者：
Nieto, Natalia