Thrombin cleavage of osteopontin controls activation of hepatic stellate cells and is essential for liver fibrogenesis

• Published in: Journal of cellular physiology Vol. 234; no. 6; pp. 8988 - 8997
• Main Authors: Cui, Guangying, Chen, Jianing, Wu, Zhongwen, Huang, Haijun, Wang, Lin, Liang, Yan, Zeng, Ping, Yang, Jiezuan, Uede, Toshimitsu, Diao, Hongyan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2019; John Wiley and Sons Inc
• Subjects: Activation; Animal models; Animals; Bile; Biocompatibility; Biomarkers; Biopsy; Carbon Tetrachloride; Case-Control Studies; Cell Movement; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Cirrhosis; Diagnostic systems; Fibrosis; full‐length osteopontin (FL‐OPN); hepatic stellate cells (HSCs); Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatitis; Hepatitis B; Humans; Integrin alpha Chains - metabolism; Integrin alpha4 - metabolism; Integrins; Liver; Liver - metabolism; Liver - pathology; Liver cirrhosis; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver diseases; liver fibrosis; Male; MAP kinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Migration; Mitogen-Activated Protein Kinases - metabolism; Neutralization; NF-kappa B; Original; Original s; Osteopontin; Osteopontin - deficiency; Osteopontin - genetics; Osteopontin - metabolism; Patients; Peptide Fragments - metabolism; Peptides; Proteins; Rodents; Signal transduction; Stellate cells; Thrombin; Thrombin - metabolism; thrombin‐cleaved osteopontin (Thr‐OPN); Up-Regulation; full-length osteopontin (FL-OPN); integrins; liver fibrosis; thrombin-cleaved osteopontin (Thr-OPN); hepatic stellate cells (HSCs)
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27571

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. Thrombin‐cleaved osteopontin (Thr‐OPN), not full‐length OPN (FL‐OPN), was critically involved in the pathogenesis of liver fibrosis by α9 and α4 integrins via mitogen‐activated protein (MAP) kinase and nuclear factor (NF‐κB) signaling pathway, thus representing a novel diagnostic biomarker and treatment target for liver cirrhosis.