Abstract
Liver biopsy is the current reliable way of evaluating liver fibrosis. However, no specific sera biomarker could be applied in clinical diagnosis. As the pivotal role of osteopontin (OPN) reported in numerous liver diseases, thrombin‐cleaved OPN (Thr‐OPN) exposes an integrin‐binding motif that promoted biological functions. Herein, we investigated the potential of Thr‐OPN in liver fibrosis. Using patient samples, mouse models and hepatic stellate cells (HSCs), we analyzed the involvement of Thr‐OPN in liver fibrosis. The result showed that, first, Thr‐OPN level was significantly higher in patients with liver cirrhosis than that in patients with chronic hepatitis B and healthy controls. Thr‐OPN level was positively correlated with liver fibrosis degree in clinical samples. Then in mouse models, it showed a similar correlation between hepatic Thr‐OPN levels and liver fibrosis degree. Thr‐OPN peptides exacerbated liver fibrosis in OPN‐deficient mice, whereas the neutralization of Thr‐OPN alleviated liver fibrosis in wild‐type mice. Furthermore, when compared with full‐length OPN (FL‐OPN), Thr‐OPN exhibited a greater ability to promote HSC activation, proliferation, and migration via mitogen‐activated protein (MAP) kinase and nuclear factor (NF)‐κB pathways. In conclusion, Thr‐OPN, not FL‐OPN, was critically involved in the exacerbation of liver fibrosis by α9 and α4 integrins via MAP kinase and NF‐κB signaling pathway, thus representing a novel diagnostic biomarker and treatment target for liver cirrhosis.
Highlights
Liver cirrhosis (LC) is the end stage of chronic liver disease that results from liver injury of a variety of etiologies
We examined whether thrombin‐cleaved osteopontin (Thr‐OPN) played a pivotal role in the pathogenesis of liver fibrosis
We found higher expression of Thr‐OPN in patients with LC compared with that in patients with chronic hepatitis B (CHB), whereas there was no difference between the levels detected in patients with CHB and healthy volunteers
Summary
Liver cirrhosis (LC) is the end stage of chronic liver disease that results from liver injury of a variety of etiologies. The transition from chronic liver disease to cirrhosis is caused by repeated liver injury and wound‐healing. This process is associated with the necrosis or apoptosis of hepatocytes, regeneration of hepatocytes, and non–parenchymal cells and extracellular matrix (ECM) deposition (Bataller & Brenner, 2005). Local macrophages and hepatic stellate cells (HSCs) are activated after necrosis. The full‐length form of OPN (FL‐OPN), which contains an Arg‐Gly‐ Asp (RGD) sequence, has diverse functions, including activation of T cells and macrophages, cell adhesion, chemotaxis, and immunomodulation through interaction with integrins such as αvβ and αvβ (Uchinaka et al, 2015; Uede, 2011; Yamamoto et al, 2003). In this study, we investigated the contribution of Thr‐OPN to liver fibrosis and assessed whether Thr‐OPN could be potentially used to stratify liver fibrosis severity
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