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1
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Zhang X, Cheung KS, Mak LY, Tan KCB, Kung AWC, Wong ICK, Cheung CL. Low Bone Mineral Density as a Risk Factor for Liver Cirrhosis. J Clin Endocrinol Metab 2025; 110:e276-e282. [PMID: 38574168 DOI: 10.1210/clinem/dgae223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/19/2024] [Accepted: 04/03/2024] [Indexed: 04/06/2024]
Abstract
CONTEXT Bone metabolism interplays with liver metabolism, also known as the liver-bone axis. Osteoporosis is a common complication of cirrhosis, but whether bone mineral density (BMD) can predict cirrhosis development is unknown. OBJECTIVE This study aims to investigate the relationship between BMD and the risk of incident cirrhosis in the Hong Kong Osteoporosis Study (HKOS). METHODS BMD was measured at the lumbar spine, femoral neck, total hip, and trochanter of 7752 participants by dual-energy x-ray absorptiometry (DXA), and the incidence of cirrhosis and mortality were followed by linking to the territory-wide electronic health records database. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CI. RESULTS With a median follow-up of 18.43 years, 42 incident cirrhosis were identified. Higher BMD T-scores at the femoral neck, total hip, and trochanter were significantly associated with a reduced risk of cirrhosis (femoral neck: HR 0.56; 95% CI, 0.39-0.82; total hip: HR 0.60; 95% CI, 0.44-0.82; trochanter: HR 0.63; 95% CI, 0.46-0.88). Similar associations were observed in participants without risk factors of cirrhosis at the baseline and further adjusting for the baseline level of alkaline phosphatase, albumin, and alanine transaminase. Consistent relationships in multiple sensitivity analyses suggest the robustness of the results. CONCLUSION Low BMD could be a novel risk factor and early predictor for cirrhosis, with consistent associations observed in multiple sensitivity analyses.
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Affiliation(s)
- Xiaowen Zhang
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
| | - Ka-Shing Cheung
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - Lung-Yi Mak
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Kathryn C B Tan
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
| | - Annie W C Kung
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
| | - Ian Chi-Kei Wong
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
- Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Pak Shek Kok, Hong Kong Special Administrative Region, China
- Research Department of Practice and Policy, School of Pharmacy, University College London, London WC1N 1AX, UK
| | - Ching-Lung Cheung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
- Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Pak Shek Kok, Hong Kong Special Administrative Region, China
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2
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Bybee G, Moeun Y, Wang W, Kharbanda KK, Poluektova LY, Kidambi S, Osna NA, Ganesan M. Increased liver stiffness promotes hepatitis B progression by impairing innate immunity in CCl4-induced fibrotic HBV + transgenic mice. Front Immunol 2023; 14:1166171. [PMID: 37600826 PMCID: PMC10435739 DOI: 10.3389/fimmu.2023.1166171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Background Hepatitis B virus (HBV) infection develops as an acute or chronic liver disease, which progresses from steatosis, hepatitis, and fibrosis to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). An increased stromal stiffness accompanies fibrosis in chronic liver diseases and is considered a strong predictor for disease progression. The goal of this study was to establish the mechanisms by which enhanced liver stiffness regulates HBV infectivity in the fibrotic liver tissue. Methods For in vitro studies, HBV-transfected HepG2.2.15 cells were cultured on polydimethylsiloxane gels coated by polyelectrolyte multilayer films of 2 kPa (soft) or 24 kPa (stiff) rigidity mimicking the stiffness of the healthy or fibrotic liver. For in vivo studies, hepatic fibrosis was induced in C57Bl/6 parental and HBV+ transgenic (HBVTg) mice by injecting CCl4 twice a week for 6 weeks. Results We found higher levels of HBV markers in stiff gel-attached hepatocytes accompanied by up-regulated OPN content in cell supernatants as well as suppression of anti-viral interferon-stimulated genes (ISGs). This indicates that pre-requisite "fibrotic" stiffness increases osteopontin (OPN) content and releases and suppresses anti-viral innate immunity, causing a subsequent rise in HBV markers expression in hepatocytes. In vitro results were corroborated by data from HBVTg mice administered CCl4 (HBVTg CCl4). These mice showed higher HBV RNA, DNA, HBV core antigen (HBcAg), and HBV surface antigen (HBsAg) levels after liver fibrosis induction as judged by a rise in Col1a1, SMA, MMPs, and TIMPs mRNAs and by increased liver stiffness. Importantly, CCl4-induced the pro-fibrotic activation of liver cells, and liver stiffness was higher in HBVTg mice compared with control mice. Elevation of HBV markers and OPN levels corresponded to decreased ISG activation in HBVTg CCl4 mice vs HBVTg control mice. Conclusion Based on our data, we conclude that liver stiffness enhances OPN levels to limit anti-viral ISG activation in hepatocytes and promote an increase in HBV infectivity, thereby contributing to end-stage liver disease progression.
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Affiliation(s)
- Grace Bybee
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Youra Moeun
- Department of Chemical and Biomolecular Engineering, University of Nebraska at Lincoln, Lincoln, NE, United States
| | - Weimin Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Srivatsan Kidambi
- Department of Chemical and Biomolecular Engineering, University of Nebraska at Lincoln, Lincoln, NE, United States
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
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3
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Du TY, Gao YX, Zheng YS. Identification of key genes related to immune infiltration in cirrhosis via bioinformatics analysis. Sci Rep 2023; 13:1876. [PMID: 36725885 PMCID: PMC9892033 DOI: 10.1038/s41598-022-26794-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 12/20/2022] [Indexed: 02/03/2023] Open
Abstract
Cirrhosis is the most common subclass of liver disease worldwide and correlated to immune infiltration. However, the immune-related molecular mechanism underlying cirrhosis remains obscure. Two gene expression profiles GSE89377 and GSE139602 were investigated to identify differentially expressed genes (DEGs) related to cirrhosis. Enrichment analysis for DEGs was conducted. Next, the immune infiltration of DEGs was evaluated using CIBERSORT algorithm. The hub DEGs with tight connectivity were identified using the String and Cytoscape databases, and the expression difference of these hub genes between normal liver and cirrhosis samples was determined. Moreover, in order to evaluate the discriminatory ability of hub genes and obtained the area under the receiver operating characteristic curve values in the GSE89377 and GSE139602 datasets. Finally, the association between hub DEGs and immune cell infiltration was explored by Spearman method. Among the 299 DEGs attained, 136 were up-regulated and 163 were down-regulated. Then the enrichment function analysis of DEGs and CIBERSORT algorithm showed significant enrichment in immune and inflammatory responses. And four hub DEGs (ACTB, TAGLN, VIM, SOX9) were identified, which also showed a diagnostic value in the GSE89377 and GSE 139,602 datasets. Finally, the immune infiltration analysis indicated that, these hub DEGs were highly related to immune cells. This study revealed key DEGs involved in inflammatory immune responses of cirrhosis, which could be used as biomarkers for diagnosis or therapeutic targets of cirrhosis.
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Affiliation(s)
- Tong-Yue Du
- Department of Critical Care Medicine, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, No.-1-1, Zhongfu Road, Nanjing, 210003, China
| | - Ya-Xian Gao
- Department of Critical Care Medicine, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, No.-1-1, Zhongfu Road, Nanjing, 210003, China
| | - Yi-Shan Zheng
- Department of Critical Care Medicine, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, No.-1-1, Zhongfu Road, Nanjing, 210003, China.
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4
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Hattori T, Iwasaki-Hozumi H, Bai G, Chagan-Yasutan H, Shete A, Telan EF, Takahashi A, Ashino Y, Matsuba T. Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases. Biomedicines 2021; 9:biomedicines9081006. [PMID: 34440210 PMCID: PMC8394573 DOI: 10.3390/biomedicines9081006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022] Open
Abstract
Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with various infectious diseases, such as adult T-cell leukemia, Mycobacterium tuberculosis (TB), hepatitis virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coronavirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or OPN-Arg168 [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase B2 or carboxypeptidase N removes Arg168 from OPN-R to OPN-Leu167 (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies against infectious diseases.
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Affiliation(s)
- Toshio Hattori
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
- Correspondence: ; Tel./Fax: +81-866-22-9469
| | - Hiroko Iwasaki-Hozumi
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Gaowa Bai
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Haorile Chagan-Yasutan
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
- Mongolian Psychosomatic Medicine Department, International Mongolian Medicine Hospital of Inner Mongolia, Hohhot 010065, China
| | - Ashwnini Shete
- ICMR-National AIDS Research Institute, 73 G-Block, MIDC, Bhosari, Pune 411026, India;
| | - Elizabeth Freda Telan
- STD AIDS Cooperative Central Laboratory, San Lazaro Hospital, Manila 1003, Philippines;
| | - Atsushi Takahashi
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Yugo Ashino
- Department of Respiratory Medicine, Sendai City Hospital, Sendai 982-8502, Japan;
| | - Takashi Matsuba
- Department of Animal Pharmaceutical Science, School of Pharmaceutical Science, Kyusyu University of Health and Welfare, Nobeoka 882-8508, Japan;
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Suri A, Singh N, Bansal SK. A Study on the Serum γ-Glutamyltranspeptidase and Plasma Osteopontin in Alcoholic Liver Disease. J Lab Physicians 2021; 14:101-108. [PMID: 36032990 PMCID: PMC9417738 DOI: 10.1055/s-0041-1729479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background
Alcoholic liver disease (ALD) is a major source of alcohol-related morbidity and mortality. Heavy drinkers and alcoholics may progress from fatty liver to alcoholic hepatitis to cirrhosis. The enzyme γ-glutamyltranspeptidase (GGT) is a membrane-bound glycoprotein which catalyzes the transfer of the γ-glutamyl group from γ-glutamyl peptides to other peptides, amino acids, and water. Serum GGT activity mainly attributed to hepatobiliary system and thus is an important marker of ALD. Hence the present study is conducted to estimate and correlate the levels of GGT and osteopontin (OPN) in ALD.
Aims and Objectives
The objective of this study is to estimate and correlate the levels of GGT and OPN in ALD.
Materials and Methods
Sixty clinically diagnosed cases of ALD and sixty age- and gender-matched healthy controls were recruited for the study. Blood samples were collected from them and serum aspartate aminotransferase, serum alanine transaminases (ALTs), serum ALP levels, and plasma OPN levels were measured. Estimation of serum aspartate transaminases (AST), ALTs, and alkaline phosphatase (ALP) was assayed by standard photometric methods in autoanalyzer ERBA-XL (EM-200) using commercially available kits. OPN was estimated by using commercial kit based on enzyme-linked immunosorbent assay.
Results
The parameters of the liver function tests such as AST, ALT, and ALP were significantly increased in patients with ALD (
p
< 0.001) when compared with the healthy control subjects. In the present study, significantly increased levels of γ-glutamyl transferases and OPN were found in patients with ALD (
p
< 0.001) when compared with the control subjects. OPN showed significant positive correlations with AST (
r
= 0.76,
p
< 0.001), ALT (
r
= 0.64,
p
< 0.001), ALP (
r
= 0.68,
p
< 0.001), and GGT (
r
= 0.61,
p
< 0.001).
Conclusion
The present study focuses on the role of GGT and OPN that are sensitive indicators of liver cell injury and are most helpful in recognizing hepatocellular diseases such as ALD, hepatitis, and liver cirrhosis. Hence, the pattern of the GGT and OPN levels elevation can be helpful diagnostically.
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Affiliation(s)
- Arpita Suri
- Department of Biochemistry, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
| | - Naveen Singh
- Department of Biochemistry, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
| | - Sanjiv Kumar Bansal
- Department of Biochemistry, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
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6
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Bruha R, Vitek L, Smid V. Osteopontin - A potential biomarker of advanced liver disease. Ann Hepatol 2021; 19:344-352. [PMID: 32005637 DOI: 10.1016/j.aohep.2020.01.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 02/07/2023]
Abstract
Cirrhosis is a primary cause of liver-related mortality and morbidity. The basic process driving chronic liver disease to cirrhosis is accelerated fibrogenesis. Although the pathogenesis of liver cirrhosis is a multifactorial process, the essential step in the evolution of liver fibrosis is the activation of hepatic stellate cells, which are the main source of collagen produced in the extracellular matrix. This activation process is mediated by multiple growth factors, cytokines, and chemokines. One of the hepatic stellate cell-activating signaling molecules (and also one associated with cell injury and fibrosis) is osteopontin (OPN). OPN concentration in the plasma has been found to be predictive of liver fibrosis in various liver diseases. OPN concentrations correlate significantly with the stage of fibrosis, liver insufficiency, portal hypertension, and the presence of hepatocellular cancer. However, due to its versatile signaling functions, OPN not only contributes to the development of liver cirrhosis, but is also implicated in the pathogenesis of other chronic hepatic diseases such as viral hepatitis, both alcoholic and non-alcoholic steatohepatitis, drug-induced liver injury, and hepatocellular cancer. Thus, the targeting of OPN pathways seems to be a promising approach in the treatment of chronic liver diseases.
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Affiliation(s)
- Radan Bruha
- Charles University in Prague, 1st Faculty of Medicine and General University Hospital, 4th Department of Internal Medicine, U Nemocnice 2, Prague, Czech Republic.
| | - Libor Vitek
- Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Institute of Medical Biochemistry and Laboratory Diagnostics, U Nemocnice 2, Prague, Czech Republic
| | - Vaclav Smid
- Charles University in Prague, 1st Faculty of Medicine and General University Hospital, 4th Department of Internal Medicine, U Nemocnice 2, Prague, Czech Republic
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7
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Kaleta B. Osteopontin and Transplantation: Where Are We Now? Arch Immunol Ther Exp (Warsz) 2021; 69:15. [PMID: 34019147 PMCID: PMC8139897 DOI: 10.1007/s00005-021-00617-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/12/2021] [Indexed: 11/26/2022]
Abstract
Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an effective therapy for a wide range of malignant and non-malignant diseases. Better understanding of transplantation immunology and the use of multi-modal immunosuppression protocols, can decrease the risk of graft failure and graft-versus-host disease (GVHD) after HSCT. Nevertheless, a major challenge of modern transplantology still seems to be finding non-invasive biomarkers for recipients selection, monitoring of allograft function, and diagnosis of rejection. Since proinflammatory cytokine osteopontin (OPN) is closely involved in regulating both adaptive and innate immune responses, as well as the pathogenesis of inflammatory and autoimmune diseases, it is likely to play an important role in organ and HSC transplantation. This review is to summarize recent advances in our knowledge about OPN function in the kidney, heart, liver, lung, and HSC transplantation. Most studies found that elevated OPN is associated with poorer graft function in kidney, heart, liver and lung recipients. Moreover, some reports suggested that this protein can play role in GVHD pathogenesis. However, due to relatively small number of similar studies, as well as some inconclusive results, future investigation in this field is needed to verify if OPN can serve as a biomarker of organ and HSC transplantation. The knowledge about such markers will promote our understanding of the mechanisms underlying graft dysfunction and posttransplant mortality. In addition, such knowledge may be helpful in the development of new treatment strategies and identification of recipients with increased risk of allograft failure.
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Affiliation(s)
- Beata Kaleta
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59 St., 02-006, Warsaw, Poland.
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8
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Liu HB, Chen QY, Wang XY, Zhang LJ, Hu LP, Harrison TJ, Wang C, Fang ZL. Infection with Hepatitis B Virus May Increase the Serum Concentrations of Osteopontin. Intervirology 2021; 64:126-134. [PMID: 33735879 PMCID: PMC8491474 DOI: 10.1159/000513687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 12/09/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Serum osteopontin (OPN) concentrations were found to be significantly increased in patients infected with hepatitis B virus (HBV) and patients with hepatocellular carcinoma (HCC). OBJECTIVE The aim of this study was to determine the association among HCC, OPN, and HBV. METHODS Two hundred and forty-one subjects were recruited and divided into 6 groups: healthy controls, asymptomatic HBsAg carriers, HBsAg (-) patients with other tumors, HBsAg (+) chronic liver disease patients, HBsAg (+) patients with HCC, and HBsAg (-) patients with HCC or liver cirrhosis (LC). Serum concentrations of OPN and HBsAg were measured and analyzed. RESULTS OPN concentrations in the HBsAg (+) HCC group were significantly higher than the healthy control group and the HBsAg (-) patients with other cancers (both p = 0.0001). The OPN concentrations of the HBsAg (-) patients with HCC or LC also did not differ significantly from those of the healthy control group (p = 0.075). There is a correlation between the titer of HBsAg and concentrations of OPN in all 3 HBsAg (+) groups (all p values <0.05). CONCLUSIONS Infection with HBV may increase the serum concentrations of OPN. The association of OPN and HCC may be not attributable to tumor development per se but, rather, to HBV infection.
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Affiliation(s)
- Hua-Bing Liu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
- School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
| | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
| | - Lu-Juan Zhang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
| | - Li-Ping Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
| | - Tim J Harrison
- Division of Medicine, UCL Medical School, London, United Kingdom
| | - Chao Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, China,
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9
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McQuitty CE, Williams R, Chokshi S, Urbani L. Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment. Front Immunol 2020; 11:574276. [PMID: 33262757 PMCID: PMC7686550 DOI: 10.3389/fimmu.2020.574276] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly via ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.
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Affiliation(s)
- Claire E. McQuitty
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
| | - Roger Williams
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
| | - Luca Urbani
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
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10
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El-Khazragy N, Khalifa MM, Salem AM, Swellam M, Hegazy M. Evaluation of Osteopontin and Pokémon genes expression in hepatitis C virus-associated hepatocellular carcinoma. J Cell Biochem 2019; 120:7439-7445. [PMID: 30417409 DOI: 10.1002/jcb.28018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 10/15/2018] [Indexed: 01/24/2023]
Abstract
Osteopontin and Pokémon genes may have an important role in the pathogenesis of different malignancies. Osteopontin is a glycoprotein of the extracellular matrix, and Pokémon is a regulator of transcription. Both have been hypothesized to be useful as therapeutic targets or diagnostic markers. We aim to assess the role of both in hepatocellular carcinoma and liver fibrosis due to hepatitis C virus (HCV) infection. We conducted our study on 50 patients and classified them into three groups-Group I: Patients with HCV-related hepatocellular carcinoma (HCC) (n = 30); Group II: Patients with hepatitis C cirrhosis (n = 10); and Group III: Patients with hepatitis C fibrosis (n = 10). We found high levels of Osteopontin and Pokémon gene expression in group I. Osteopontin levels were higher also in patients with liver fibrosis was correlated to high levels of parameters such as alpha fetoprotein and caspase. We conclude that HCC is associated with overexpression of both Osteopontin and Pokémon and that Osteopontin plays a significant role in liver fibrosis due to hepatitis C infection.
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Affiliation(s)
- Nashwa El-Khazragy
- Department of Clinical Pathology/Hematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.,Department of Medical Research, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mona M Khalifa
- Biochemistry Department, Faculty of Science and Arts, Jazan University, Jazan, Saudi Arabia
| | - Ahmed M Salem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Menha Swellam
- High Throughput Molecular and Genetic laboratory, Center for Excellence for Advanced Sciences, Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre
| | - Marwa Hegazy
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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11
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SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis. Sci Rep 2018; 8:17905. [PMID: 30559459 PMCID: PMC6297163 DOI: 10.1038/s41598-018-36037-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 10/27/2018] [Indexed: 02/07/2023] Open
Abstract
Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.
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12
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Sobhy A, Fakhry M M, A Azeem H, Ashmawy AM, Omar Khalifa H. Significance of biglycan and osteopontin as non-invasive markers of liver fibrosis in patients with chronic hepatitis B virus and chronic hepatitis C virus. J Investig Med 2018; 67:681-685. [PMID: 30385593 DOI: 10.1136/jim-2018-000840] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2018] [Indexed: 12/17/2022]
Abstract
Several studies were performed to evaluate the degree of liver fibrosis by non-invasive markers. We aimed to assess the diagnostic value of both biglycan (BGN) and osteopontin (OPN) as non-invasive markers of hepatic fibrosis in patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study was performed on 100 patients with CHB virus, 100 patients with CHC virus and 100 normal controls. All participants were subjected to the following laboratory tests: hemoglobin, platelet, alanine aminotransferase, aspartate aminotransferase, albumin, international normalized ratio, HBs Ag, hepatitis C virus (HCV) antibody, hepatitis B virus DNA, HCV RNA, liver biopsy, BGN and OPN. We found that BGN level was significantly increased in the CHB group compared with the controls (p<0.001), but the level was not different between the CHC group and the controls (p<0.96). OPN was increased in both the CHB and CHC groups compared with the controls (p<0.001). Positive correlation was found between fibrosis stages and BGN level of the CHB group (r=0.64; p<0.001) and between fibrosis stages and OPN level of the CHB (r=0.63; p<0.001) and CHC (r=0.59; p<0.03) groups. The area under the curve (AUC), sensitivity and specificity of BGN were 1.0, 100% and 100% in predicting fibrosis in patients with CHB, and 0.50, 26% and 78% in predicting fibrosis in patients with CHC. OPN had an AUC of 0.997, sensitivity of 96% and specificity of 100% in predicting fibrosis in patients with CHB, and 0.974, 96.5% and 100% in predicting fibrosis in patients with CHC. In conclusion, BGN and OPN could be considered non-invasive markers for liver fibrosis assessment.
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Affiliation(s)
- Ali Sobhy
- Clinical Pathology Department., Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Mohammed Fakhry M
- Gastroenterology and Hepatology Department, Faculty of Medicine., Al-Azhar University, Assiut
| | - Haitham A Azeem
- Internal Medicine Department, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Ahmed M Ashmawy
- Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hamed Omar Khalifa
- Public Health andCommunity Medicine Department, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
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13
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Cui G, Chen J, Wu Z, Huang H, Wang L, Liang Y, Zeng P, Yang J, Uede T, Diao H. Thrombin cleavage of osteopontin controls activation of hepatic stellate cells and is essential for liver fibrogenesis. J Cell Physiol 2018; 234:8988-8997. [PMID: 30350863 PMCID: PMC6588095 DOI: 10.1002/jcp.27571] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 09/17/2018] [Indexed: 02/05/2023]
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.
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Affiliation(s)
- Guangying Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianing Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongwen Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haijun Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiezuan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Toshimitsu Uede
- Department of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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14
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Bellan M, Castello LM, Pirisi M. Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review. J Clin Transl Hepatol 2018; 6:317-325. [PMID: 30271745 PMCID: PMC6160308 DOI: 10.14218/jcth.2018.00006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/25/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022] Open
Abstract
Repair of sustained liver injury results in fibrosis (i.e. the accumulation of extracellular matrix proteins), and ultimately the complete distortion of parenchymal architecture of the liver, which we call cirrhosis. Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases, since many clinically relevant decisions, such as starting treatment and/or monitoring for complications including hepatocellular carcinoma, may depend on it. The gold standard for fibrosis staging is liver biopsy, the role of which, however, is questioned nowadays because of cost, hazards and poor acceptance by patients. On the other hand, imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy. Making progress in this field is now more crucial than ever, since treatments for established fibrosis appear on the horizon. Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis, such as growth arrest-specific6, Mac-2-binding protein, osteopontin, placental growth factor, growth/differentiation factor 15 and hepatocyte growth factor. All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases. Here, we review the pros and cons for their use in this setting.
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Affiliation(s)
- Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Division of Internal Medicine, “Sant’Andrea Hospital”, Vercelli, Italy
- IRCAD, Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy
- *Correspondence to: Mattia Bellan, Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, Novara (NO) 28100, Italy. Tel: +39-321-3733966, Fax: +39-321-3733361, E-mail:
| | - Luigi Mario Castello
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Emergency Medicine Department, “AOU Maggiore della Carità”, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Division of Internal Medicine, “AOU Maggiore della Carità, Novara, Italy
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15
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Osteopontin Regulates Hepatitis C Virus (HCV) Replication and Assembly by Interacting with HCV Proteins and Lipid Droplets and by Binding to Receptors αVβ3 and CD44. J Virol 2018; 92:JVI.02116-17. [PMID: 29669827 DOI: 10.1128/jvi.02116-17] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/28/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) replication and assembly occur at the specialized site of endoplasmic reticulum (ER) membranes and lipid droplets (LDs), respectively. Recently, several host proteins have been shown to be involved in HCV replication and assembly. In the present study, we demonstrated the important relationship among osteopontin (OPN), the ER, and LDs. OPN is a secreted phosphoprotein, and overexpression of OPN in hepatocellular carcinoma (HCC) tissue can lead to invasion and metastasis. OPN expression is also enhanced in HCV-associated HCC. Our recent studies have demonstrated the induction, proteolytic cleavage, and secretion of OPN in response to HCV infection. We also defined the critical role of secreted OPN in human hepatoma cell migration and invasion through binding to receptors integrin αVβ3 and CD44. However, the role of HCV-induced OPN in the HCV life cycle has not been elucidated. In this study, we showed a significant reduction in HCV replication, assembly, and infectivity in HCV-infected cells transfected with small interfering RNA (siRNA) against OPN, αVβ3, and CD44. We also observed the association of endogenous OPN with HCV proteins (NS3, NS5A, NS4A/B, NS5B, and core). Confocal microscopy revealed the colocalization of OPN with HCV NS5A and core in the ER and LDs, indicating a possible role for OPN in HCV replication and assembly. Interestingly, the secreted OPN activated HCV replication, infectivity, and assembly through binding to αVβ3 and CD44. Collectively, these observations provide evidence that HCV-induced OPN is critical for HCV replication and assembly.IMPORTANCE Recently, our studies uncovered the critical role of HCV-induced endogenous and secreted OPN in migration and invasion of hepatocytes. However, the role of OPN in the HCV life cycle has not been elucidated. In this study, we investigated the importance of OPN in HCV replication and assembly. We demonstrated that endogenous OPN associates with HCV NS3, NS5A, NS5B, and core proteins, which are in close proximity to the ER and LDs. Moreover, we showed that the interactions of secreted OPN with cell surface receptors αVβ3 and CD44 are critical for HCV replication and assembly. These observations provide evidence that HCV-induced endogenous and secreted OPN play pivotal roles in HCV replication and assembly in HCV-infected cells. Taken together, our findings clearly demonstrate that targeting OPN may provide opportunities for therapeutic intervention of HCV pathogenesis.
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16
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Gerhard GS, Legendre C, Still CD, Chu X, Petrick A, DiStefano JK. Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes. J Endocr Soc 2018; 2:710-726. [PMID: 29978150 PMCID: PMC6018672 DOI: 10.1210/js.2018-00122] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 05/31/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is strongly associated with obesity and type 2 diabetes. The molecular factors underlying the development of inflammation and severe fibrosis in NASH remain largely unknown. The purpose of this study was to identify gene expression patterns related to obesity-related NASH inflammation and fibrosis. We performed sequencing-based mRNA profiling analysis of liver samples from individuals with normal histology (n = 24), lobular inflammation (n = 53), or bridging fibrosis, incomplete cirrhosis, or cirrhosis (n = 65). Hepatic expression of a subset of mRNAs was validated using an orthogonal method, analyzed in a hepatic stellate cell line, and used to identify transcriptional patterns shared by other forms of cirrhosis. We observed evidence for differential levels of 3820 and 2980 transcripts in lobular inflammation and advanced fibrosis, respectively, compared with normal histology (false discovery rate ≤0.05), including 176 genes specific to fibrosis. Functional enrichment analysis of these genes revealed participation in pathways involving cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix-receptor interaction. We identified 34 differentially expressed transcripts in comparisons of lobular inflammation and fibrosis, a proportion of which were also upregulated during activation of hepatic stellate cells. A set of 16 genes from a previous independent study of NASH bridging fibrosis/cirrhosis were replicated, several of which have also been associated with advanced fibrosis/cirrhosis due to hepatitis viruses or alcohol in human patients. Dysregulated mRNA expression is associated with inflammation and fibrosis in NASH. Advanced NASH fibrosis is characterized by distinct set of molecular changes that are shared with other causes of cirrhosis.
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Affiliation(s)
- Glenn S Gerhard
- Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | | | | | - Xin Chu
- Geisinger Obesity Institute, Danville, Pennsylvania
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17
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Modares Mousavi SR, Geramizadeh B, Anushiravani A, Ejtehadi F, Anbardar MH, Moini M. Correlation between Serum Ferritin Level and Histopathological Disease Severity in Non-alcoholic Fatty Liver Disease. Middle East J Dig Dis 2018; 10:90-95. [PMID: 30013757 PMCID: PMC6040928 DOI: 10.15171/mejdd.2018.96] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 03/09/2018] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. Recently several parameters, such as serum ferritin, have emerged as possible predictors for the severity of NAFLD and insulin sensitivity. We aimed to investigate the value of serum ferritin level as a useful biomarker for the prediction of histopathological disease severity in non-alcoholic steatohepatitis (NASH), the necro-inflammatory form of NAFLD. METHODS This was a prospective cross sectional study in which demographic, clinical, histological, laboratory, and anthropometric data of 30 adult patients with biopsy-proven NAFLD/NASH were analyzed. RESULTS In our patients population with mean age of 37.9 years and mean BMI of 26.5, statistical analysis did not show a significant difference between the three grades of steatosis in the mean ferritin levels (p = 0.559). It was also observed that ferritin level did not have a significant correlation with the stage of fibrosis (p = 0.228). The mean transferrin saturation did not show significant difference in different stages and grades of NASH (p = 0.260 and 0.944, respectively), either. CONCLUSION Serum ferritin level may not be useful as a single marker for the prediction of histopathological severity of disease in young patients with NASH who are not morbidly obese.
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Affiliation(s)
- Seyed Reza Modares Mousavi
- Division of Gastroenterology, Department of Internal Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz, Iran
| | - Bita Geramizadeh
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Anushiravani
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fardad Ejtehadi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Maryam Moini
- Non-communicable Disease Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Int J Mol Sci 2017; 19:ijms19010007. [PMID: 29267211 PMCID: PMC5795959 DOI: 10.3390/ijms19010007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.
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19
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Liu L, Lu J, Ye C, Lin L, Zheng S, Zhang H, Lan Q, Xue Y. Serum osteopontin is a predictor of prognosis for HBV-associated acute-on-chronic liver failure. Biomed Rep 2017; 8:166-171. [PMID: 29435276 DOI: 10.3892/br.2017.1027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/11/2017] [Indexed: 12/16/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome with a high rate of short-term mortality, and clinically it is important to identify patients at high risk of mortality. The present study evaluated the value of osteopontin (OPN) in the prediction of 90-day mortality in patients with ACLF. A total of 54 patients with HBV-associated ACLF were enrolled, and serum OPN levels were determined in a prospective, observational study design. Survival analysis was performed using Kaplan-Meier curves, and multivariate Cox proportional hazards regression was used to analyze independent risk factors of mortality. Serum OPN was significantly higher in HBV-ACLF patients compared with patients with chronic hepatitis B and healthy controls (both P<0.01), and furthermore, was higher in those patients who succumbed to HBV-ACLF compared with surviving patients (P<0.05). OPN level positively correlated with total bilirubin (r=0.554, P<0.001), Model for End-Stage Liver Disease (MELD) score (r=0.234, P=0.038), MELD-Na score (r=0.379, P=0.005) and monocyte count (r=0.282, P=0.039), and OPN was an independent risk factor for 90-day mortality in ACLF (P=0.021, odds ratio=1.104, 95% confidence interval: 1.003-1.116). Furthermore, ACLF patients were stratified into three groups according to serum OPN levels (low mortality risk: <6,135 ng/ml; intermediate risk: 6,135-9,043 ng/ml; and high risk: >9,043 ng/ml), for which the 90-day mortality rates were 27.78 (5/18), 52.94 (9/17) and 73.68% (14/19), respectively, and those in the high risk had a poorer prognosis compared with the low risk group (P=0.009). In conclusion, serum OPN may be an independent risk factor associated with HBV-ACLF prognosis.
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Affiliation(s)
- Longgen Liu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Jianchun Lu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Chunyan Ye
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Lin Lin
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Pharmacy, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Shuqin Zheng
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Hongyu Zhang
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
| | - Qing Lan
- Department of Infectious Diseases, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650051, P.R. China
| | - Yuan Xue
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China.,Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
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20
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The Roles of Matricellular Proteins in Oncogenic Virus-Induced Cancers and Their Potential Utilities as Therapeutic Targets. Int J Mol Sci 2017; 18:ijms18102198. [PMID: 29065446 PMCID: PMC5666879 DOI: 10.3390/ijms18102198] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/17/2017] [Accepted: 10/18/2017] [Indexed: 12/13/2022] Open
Abstract
Matricellular proteins differ from other classical extracellular matrix proteins; for instance, they are transiently expressed as soluble proteins rather than being constitutively expressed in pathological conditions, such as acute viral infections. Accumulating studies have revealed that matricellular proteins, including osteopontin and tenascin-C, both of which interact with integrin heterodimers, are involved in inflammatory diseases, autoimmune disorders, and cancers. The concentrations of these matricellular proteins are elevated in the plasma of patients with certain types of cancers, indicating that they play important roles in oncogenesis. Chronic viral infections are associated with certain cancers, which are distinct from non-viral cancers. Viral oncogenes play critical roles in the development and progression of such cancers. It is vital to investigate the mechanisms of tumorigenesis and, particularly, the mechanism by which viral proteins induce tumor progression. Viral proteins have been shown to influence not only the viral-infected cancer cells, but also the stromal cells and matricellular proteins that constitute the extracellular matrix that surrounds tumor tissues. In this review, we summarize the recent progress on the involvement of matricellular proteins in oncogenic virus-induced cancers to elucidate the mechanism of oncogenesis and consider the possible role of matricellular proteins as therapeutic targets in virus-induced cancers.
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21
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Wen Y, Jeong S, Xia Q, Kong X. Role of Osteopontin in Liver Diseases. Int J Biol Sci 2016; 12:1121-8. [PMID: 27570486 PMCID: PMC4997056 DOI: 10.7150/ijbs.16445] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.
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Affiliation(s)
- Yankai Wen
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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22
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Bruha R, Jachymova M, Petrtyl J, Dvorak K, Lenicek M, Urbanek P, Svestka T, Vitek L. Osteopontin: A non-invasive parameter of portal hypertension and prognostic marker of cirrhosis. World J Gastroenterol 2016; 22:3441-3450. [PMID: 27022226 PMCID: PMC4806202 DOI: 10.3748/wjg.v22.i12.3441] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/03/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between osteopontin plasma concentrations and the severity of portal hypertension and to assess osteopontin prognostic value.
METHODS: A cohort of 154 patients with confirmed liver cirrhosis (112 ethylic, 108 men, age 34-72 years) were enrolled in the study. Hepatic venous pressure gradient (HVPG) measurement and laboratory and ultrasound examinations were carried out for all patients. HVPG was measured using a standard catheterization method with the balloon wedge technique. Osteopontin was measured using the enzyme-linked immunosorbent assay (ELISA) method in plasma. Patients were followed up with a specific focus on mortality. The control group consisted of 137 healthy age- and sex- matched individuals.
RESULTS: The mean value of HVPG was 16.18 ± 5.6 mmHg. Compared to controls, the plasma levels of osteopontin in cirrhotic patients were significantly higher (P < 0.001). The plasma levels of osteopontin were positively related to HVPG (P = 0.0022, r = 0.25) and differed among the individual Child-Pugh groups of patients. The cut-off value of 80 ng/mL osteopontin distinguished patients with significant portal hypertension (HVPG above 10 mmHg) at 75% sensitivity and 63% specificity. The mean follow-up of patients was 3.7 ± 2.6 years. The probability of cumulative survival was 39% for patients with HVPG > 10 mmHg and 65% for those with HVPG ≤ 10 mmHg (P = 0.0086, odds ratio (OR), 2.92, 95% confidence interval (CI): 1.09-7.76). Osteopontin showed a similar prognostic value to HVPG. Patients with osteopontin values above 80 ng/mL had significantly lower cumulative survival compared to those with osteopontin ≤ 80 ng/mL (37% vs 56%, P = 0.00035; OR = 2.23, 95%CI: 1.06-4.68).
CONCLUSION: Osteopontin is a non-invasive parameter of portal hypertension that distinguishes patients with clinically significant portal hypertension. It is a strong prognostic factor for survival.
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Jang ES, Jeong SH, Kim JW, Choi YS, Leissner P, Brechot C. Diagnostic Performance of Alpha-Fetoprotein, Protein Induced by Vitamin K Absence, Osteopontin, Dickkopf-1 and Its Combinations for Hepatocellular Carcinoma. PLoS One 2016; 11:e0151069. [PMID: 26986465 PMCID: PMC4795737 DOI: 10.1371/journal.pone.0151069] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/23/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND & AIMS Alpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. As complementary biomarkers, protein induced by vitamin K absence (PIVKA-II), osteopontin (OPN), and Dickkopf-1 (DKK-1) have been proposed. This study aimed to perform a head-to-head comparison of the diagnostic performance of AFP, PIVKA-II, OPN and DKK-1 as single or in combination to seek the best biomarker or panel, and to investigate the clinical factors affecting their performance. METHODS Using 401 stored plasma samples obtained from 208 HCC patients and 193 liver cirrhosis control patients, plasma AFP, PIVKA-II, OPN and DKK-1 levels were measured by ELISA, and receiver operating characteristic curve analyses were performed for each biomarker and for every combination of two to four markers. RESULTS Of the four biomarkers, AFP showed the highest area under the curve (0.786). The sensitivity and specificity for each single biomarker was 62% and 90.2% (AFP>20 ng/mL), 51.0% and 91.2% (PIVKA-II>10 ng/mL), 46.2% and 80.3% (OPN>100 ng/mL), and 50.0% and 80.8% (DKK-1>500 pg/mL), respectively. Among the combinations of two biomarkers, AFP>20 ng/mL or DKK-1>500 pg/mL showed the best diagnostic performance (sensitivity 78.4%, specificity 72.5%). Triple or quadruple combination did not improve the diagnostic performance further. The patient's age, etiology and tumor invasiveness of HCC affected the performance of each marker. CONCLUSIONS AFP was the most useful single biomarker for HCC diagnosis, and the combined measurement of AFP and DKK-1 could maximize the diagnostic yield. Clinical decision should be based on the consideration of various factors affecting the diagnostic performance of each biomarker. Efforts to seek novel HCC biomarkers should be continued.
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Affiliation(s)
- Eun Sun Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Yun Suk Choi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Philippe Leissner
- Medical Diagnostics Discovery Department, bioMérieux, Marcy l’Etoile, France
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Fouad SA, Mohamed NAG, Fawzy MW, Moustafa DA. Plasma Osteopontin Level in Chronic Liver Disease and Hepatocellular Carcinoma. HEPATITIS MONTHLY 2015; 15:e30753. [PMID: 26500684 PMCID: PMC4612688 DOI: 10.5812/hepatmon.30753] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 07/31/2015] [Accepted: 08/16/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Osteopontin (OPN) is a secreted glycoprotein and is frequently associated with various tumors. OBJECTIVES We sought to investigate the clinical usefulness of the level of plasma OPN, compared to α-fetoprotein (AFP), as a biomarker for hepatocellular carcinoma (HCC) and to evaluate its diagnostic value in nonalcoholic fatty liver disease (NAFLD) and its relationship with clinical and laboratory features of HCC and NAFLD. PATIENTS AND METHODS The study was performed on 120 subjects classified into 5 groups: Group I included 25 chronic non-cirrhotic hepatitis C virus (HCV)-infected patients; Group II encompassed 25 patients with chronic HCV infection with liver cirrhosis; Group III comprised 25 patients with chronic HCV with liver cirrhosis and HCC; Group IV was comprised of 25 patients with NAFLD; and Group V consisted of 20 healthy age- and sex-matched controls. All the participants were subjected to history taking and clinical and abdominal ultrasonographic examinations as well as the following laboratory investigations: liver function tests, complete blood count, blood sugar, hepatitis B surface antigen, hepatitis C virus antibodies, HCV-RNA by qualitative polymerase chain reaction (for Groups I, II, and III) and serum AFP and plasma OPN levels. RESULTS There were statistically significant differences in plasma OPN levels between the HCC group (401 ± 72 ng/mL) and the other groups, between the cirrhotic group (258.3 ± 35 ng/mL) and the non-cirrhotic group (HCV group, 168.7 ± 41 ng/mL; fatty liver group, 106.7 ± 35 ng/mL), and between the chronic non-cirrhotic HCV group and the fatty liver group (I and IV) and the controls (35.1 ± 6 ng/mL). In the HCC group, the diagnostic value of OPN was comparable to that of AFP at a cutoff value of 280 ng/mL, achieving sensitivity, specificity, and overall accuracy of 100%, 98%, and 96%, respectively. Regarding the validity of plasma OPN as a predictor of fatty change, our results revealed a diagnostic accuracy of 50% with 70% sensitivity, 45% specificity, 50% positive predictive value, and 75% negative predictive value at a cutoff value of 134 ng/mL. CONCLUSIONS Plasma OPN is comparable to AFP as a diagnostic marker and is related to the severity of liver involvement in HCC patients. Plasma OPN is of diagnostic potential value in NAFLD.
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Affiliation(s)
- Shawky Abdelhamid Fouad
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
- Corresponding Author: Shawky Abdelhamid Fouad, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt. Tel: +20-01223658902, E-mail:
| | | | - Mary Wadie Fawzy
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Doaa Ali Moustafa
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
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Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni. Clin Sci (Lond) 2015. [PMID: 26201095 PMCID: PMC4558314 DOI: 10.1042/cs20150117] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Schistosomal egg antigens induce host bile ductular cells to proliferate and produce osteopontin (OPN), a pro-fibrogenic factor that stimulates hepatic stellate cells to become myofibroblasts. The numbers of OPN-producing bile ductules correlate with fibrogenesis and portal hypertension in humans and mice. Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity.
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Simão A, Madaleno J, Silva N, Rodrigues F, Caseiro P, Costa JN, Carvalho A. Plasma osteopontin is a biomarker for the severity of alcoholic liver cirrhosis, not for hepatocellular carcinoma screening. BMC Gastroenterol 2015; 15:73. [PMID: 26122937 PMCID: PMC4487194 DOI: 10.1186/s12876-015-0307-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/24/2015] [Indexed: 12/11/2022] Open
Abstract
Background Implementation of surveillance programs for at-risk populations and identification of biomarkers for early hepatocellular carcinoma (HCC) detection are a major public health goal. Recently, osteopontin (OPN) has attracted attention as a promising biomarker, with some potential advantages compared to alpha-fetoprotein (AFP), but its role in the context of alcoholic cirrhosis has never been assessed. The aims of this study are to assess the utility of plasma OPN in the diagnosis of HCC in alcoholic cirrhotic patients and to investigate whether increased values are due to the tumor or underlying liver disease severity. Methods A total of 90 consecutively alcoholic cirrhosis patients, observed between Jun 2013 and May 2014 at a Liver Disease Unit, were included and divided into two groups: 45 without (group I) and 45 with HCC (group II). Plasma levels of OPN (ELISA, Immuno-Biological Laboratories, Gunma, Japan) and AFP (IMMULITE® 2000 AFP, Siemens Healthcare Diagnostics, Tarrytown, New York) were assessed. The diagnostic accuracy of each marker was evaluated using Receiver-Operating Characteristic (ROC) curve analysis (AUC) and its 95 % Confidence Interval (CI). Results Plasma OPN levels in group I patients (1176.28 +/–744.59 ng/mL) weren’t significantly different from those of group II (1210.75 +/–800.60 ng/mL) (p = 0.826). OPN levels significantly increased with advancing BCLC tumor stage and with advancing Child-Pugh class, in both groups. Comparing the two groups, AUC for OPN and AFP were 0.51 (95 % CI: 0.39–0.63) and 0.79 (95 % CI: 0.70–0.89), respectively. Based on the ROC analysis, there were no satisfactory cut-off values for OPN that would distinguish patients with from those without tumour. Conclusions Despite having a correlation with BCLC stage, the same was observed with progressive deterioration of underlying liver function in terms of Child-Pugh class and MELD score, and isn’t a useful diagnostic biomarker for HCC in alcoholic cirrhotic patients, particularly in the early stages. AFP confirms the performance evidenced in other studies, being superior to OPN. Searching more specific biomarkers for early diagnosis of HCC in alcoholic cirrhosis is still warranted.
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Affiliation(s)
- Adélia Simão
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - João Madaleno
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Nuno Silva
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Fernando Rodrigues
- Clinical Pathology-Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - Paula Caseiro
- Clinical Pathology-Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - José Nascimento Costa
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Armando Carvalho
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
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Matsue Y, Tsutsumi M, Hayashi N, Saito T, Tsuchishima M, Toshikuni N, Arisawa T, George J. Serum osteopontin predicts degree of hepatic fibrosis and serves as a biomarker in patients with hepatitis C virus infection. PLoS One 2015; 10:e0118744. [PMID: 25760884 PMCID: PMC4356538 DOI: 10.1371/journal.pone.0118744] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 01/12/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND & AIMS Osteopontin (OPN) is a matricellular protein that upregulates during pathogenesis of hepatic fibrosis. The present study was aimed to evaluate whether serum OPN could be used as a biomarker to assess the degree of hepatic fibrosis in patients with hepatitis C virus (HCV) infection. METHODS Needle biopsy was performed on HCV patients and scored as zero fibrosis (F0), mild fibrosis (F1), moderate fibrosis (F2), severe fibrosis (F3) and liver cirrhosis (F4) based on Masson's trichrome and α-smooth muscle actin (α-SMA) staining. Serum OPN levels were measured using ELISA and correlated with the degree of fibrosis. Furthermore, the OPN values were correlated and evaluated with platelets count, serum hyaluronic acid (HA), and collagen type IV and subjected to receiver operating characteristic (ROC) curve analysis. RESULTS Serum OPN levels were remarkably increased from F0 through F4 in a progressive manner and the differences were significant (P < 0.001) between each group. The data were highly correlated with the degree of hepatic fibrosis. The ROC curve analysis depicted that serum OPN is an independent risk factor and an excellent biomarker and a prognostic index in HCV patients. CONCLUSIONS The results of the present study indicate that serum OPN levels reflect the degree of hepatic fibrosis and could be used as a biomarker to assess the stage of fibrosis in HCV patients which would help to reduce the number of liver biopsies. Furthermore, serum OPN serves as a prognostic index towards the progression of hepatic fibrosis to cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Yasuhiro Matsue
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Mikihiro Tsutsumi
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Nobuhiko Hayashi
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Takashi Saito
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Mutsumi Tsuchishima
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Nobuyuki Toshikuni
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Tomiyasu Arisawa
- Department of Gastroenterology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Joseph George
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
- * E-mail:
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Abstract
The Hedgehog (Hh) signaling pathway plays a key role during embryogenesis and tissue regeneration. Recently, studies revealed that overactivated Hh signaling leads to fibrogenesis in many types of tissues. The activation of Hh signaling is involved in the epithelial-mesenchymal transition and excessive extracellular matrix deposition. Blockade of Hh signaling abolishes the induction of the epithelial-mesenchymal transition and ameliorates tissue fibrosis. Therefore, new therapeutic targets to alleviate fibrosis based on the Hh signaling have attracted a great deal of attention. This is a new strategy for treating fibrosis and other related diseases. In this review, we discuss the crucial role of Hh signaling in fibrogenesis to provide a better understanding of their relationship and to encourage the study of novel targeted therapies.
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Affiliation(s)
- Liping Hu
- Department of Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (L.H., X.L., H.L.); Department of Laboratory Medicine, JianLi County People's Hospital, Jingzhou (L.H.); and Wenzhou Key Laboratory of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (B.C., Y.B.), People's Republic of China
| | - Xiangyang Lin
- Department of Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (L.H., X.L., H.L.); Department of Laboratory Medicine, JianLi County People's Hospital, Jingzhou (L.H.); and Wenzhou Key Laboratory of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (B.C., Y.B.), People's Republic of China
| | - Hong Lu
- Department of Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (L.H., X.L., H.L.); Department of Laboratory Medicine, JianLi County People's Hospital, Jingzhou (L.H.); and Wenzhou Key Laboratory of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (B.C., Y.B.), People's Republic of China
| | - Bicheng Chen
- Department of Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (L.H., X.L., H.L.); Department of Laboratory Medicine, JianLi County People's Hospital, Jingzhou (L.H.); and Wenzhou Key Laboratory of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (B.C., Y.B.), People's Republic of China
| | - Yongheng Bai
- Department of Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (L.H., X.L., H.L.); Department of Laboratory Medicine, JianLi County People's Hospital, Jingzhou (L.H.); and Wenzhou Key Laboratory of Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou (B.C., Y.B.), People's Republic of China
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Meta-analysis of the prognostic and diagnostic significance of serum/plasma osteopontin in hepatocellular carcinoma. J Clin Gastroenterol 2014; 48:806-14. [PMID: 24247813 DOI: 10.1097/mcg.0000000000000018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOALS The aim of this study was to perform a meta-analysis to evaluate the prognostic and diagnostic significance of serum/plasma osteopontin (OPN) in hepatocellular carcinoma (HCC). BACKGROUND The prognostic and diagnostic value of serum/plasma OPN) in HCC remain controversial. STUDY Eligible studies were identified through a systematic literature search. A meta-analysis of 8 studies (4 for prognosis and 4 for diagnosis, 1399 patients) was performed to estimate the association between serum/plasma-based OPN elevation and overall survival (OS) and disease-free survival (DFS) in HCC patients, and to evaluate the accuracy of plasma OPN and α-fetoprotein (AFP) in the diagnosis of HCC. Subgroup analyses were also performed in the meta-analysis. RESULTS We found that serum/plasma-based OPN elevation was significantly associated with poor OS (HR, 1.96; 95% CI, 1.47-2.61; P<0.00001) and DFS (HR, 1.80; 95% CI, 1.43-2.26; P<0.00001) in HCC. The summary estimates for plasma OPN and AFP in diagnosing HCC in the studies included were as follows: sensitivity, 88% (95% CI, 84%-91%) versus 68% (95% CI, 63%-73%); specificity, 87% (95% CI, 83%-90%) versus 97% (95% CI, 94%-99%); diagnostic odds ratio, 62.87 (95% CI, 10.90-362.60) versus 49.09 (95% CI, 11.36-212.10); and area under SROS, 0.91 (95% CI, 0.85-0.97) versus 0.68 (95% CI, 0.45-1.03). CONCLUSIONS The current evidence indicates that serum/plasma-based OPN seems to have significant predictive ability for estimating survival in HCC, and plasma OPN has a comparable accuracy to AFP for the diagnosis of HCC, although the diagnostic value of plasma OPN for early or AFP-negative HCC remains to be assessed by further studies.
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Yang P, Markowitz GJ, Wang XF. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev 2014; 1:396-412. [PMID: 25741453 DOI: 10.1093/nsr/nwu038] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In contrast to a majority of cancer types, the initiation of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue, with one of the most prevalent etiological factors being hepatitis B virus (HBV). Transformation of the liver in HBV-associated HCC often follows from or accompanies long-term symptoms of chronic hepatitis, inflammation and cirrhosis, and viral load is a strong predictor for both incidence and progression of HCC. Besides aiding in transformation, HBV plays a crucial role in modulating the accumulation and activation of both cellular components of the microenvironment, such as immune cells and fibroblasts, and non-cellular components of the microenvironment, such as cytokines and growth factors, markedly influencing disease progression and prognosis. This review will explore some of these components and mechanisms to demonstrate both underlying themes and the inherent complexity of these interacting systems in the initiation, progression, and metastasis of HBV-positive HCC.
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Affiliation(s)
- Pengyuan Yang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA ; CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Geoffrey J Markowitz
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Xiao-Fan Wang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
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Imran M, Manzoor S, Parvaiz F. Predictive potential of IL-18 -607 and osteopontin -442 polymorphism in interferon-based therapy of HCV infection in the Pakistani population. Viral Immunol 2014; 27:404-11. [PMID: 25198668 DOI: 10.1089/vim.2014.0044] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The adaptive immune system plays an important role in response to interferon plus ribavirin treatment of hepatitis C virus (HCV) infection. Cytokines play a significant role in the adaptive immune system. The production of cytokines may be regulated by single nucleotide polymorphisms (SNPs). This study was designed to examine the correlation of some important SNPs of cytokines with interferon plus ribavirin treatment of HCV infection in the Pakistani population. We followed 140 chronic HCV-infected patients in our study. All of these patients had completed their planned course of interferon plus ribavirin treatment. We also considered 120 healthy subjects as controls. The detection of interleukin-18 (IL-18) SNPs was performed by tetra-primers amplification-refectory mutation system polymerase chain reaction, while for genotyping of osteopontin (OPN), transforming growth factor beta (TGFβ), and N-acetylgalactosaminyltransferase 8 (GALNT8) SNPs, allele-specific polymerase chain reaction was performed. The distribution of the IL-18 -607AA genotype varied significantly between healthy control and patient groups. Its distribution was significantly high in healthy subjects than HCV patients (p = 0.031), signifying its potential involvement in the natural clearance of HCV infection. The occurrence of the -607AA genotype of IL-18 was also significantly higher in the sustained virological group (SVR) than in the nonresponder (NR) group (p = 0.046), highlighting its protective involvement in the treatment outcome of chronic HCV infection. The frequency of the OPN -442TT genotype was higher in the SVR group than in the NR group (p = 0.034), indicating a significant possible role of this genotype in therapy for HCV infection. No important association was found between TGFβ and GALNT8 genotypes and the natural clearance and treatment response of HCV infection. IL-18 -607AA and OPN -442TT genotypes can be used as positive predictive markers of interferon plus ribavirin treatment of HCV infection in the Pakistani population.
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Affiliation(s)
- Muhammad Imran
- Atta-ur-Rahman School of Applied Bio-Sciences, Department of Healthcare Biotechnology, National University of Sciences and Technology (NUST) , Islamabad, Pakistan
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Arriazu E, Ruiz de Galarreta M, Cubero FJ, Varela-Rey M, Pérez de Obanos MP, Leung TM, Lopategi A, Benedicto A, Abraham-Enachescu I, Nieto N. Extracellular matrix and liver disease. Antioxid Redox Signal 2014; 21:1078-97. [PMID: 24219114 PMCID: PMC4123471 DOI: 10.1089/ars.2013.5697] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
SIGNIFICANCE The extracellular matrix (ECM) is a dynamic microenvironment that undergoes continuous remodeling, particularly during injury and wound healing. Chronic liver injury of many different etiologies such as viral hepatitis, alcohol abuse, drug-induced liver injury, obesity and insulin resistance, metabolic disorders, and autoimmune disease is characterized by excessive deposition of ECM proteins in response to persistent liver damage. CRITICAL ISSUES This review describes the main collagenous and noncollagenous components from the ECM that play a significant role in pathological matrix deposition during liver disease. We define how increased myofibroblasts (MF) from different origins are at the forefront of liver fibrosis and how liver cell-specific regulation of the complex scarring process occurs. RECENT ADVANCES Particular attention is paid to the role of cytokines, growth factors, reactive oxygen species, and newly identified matricellular proteins in the regulation of fibrillar type I collagen, a field to which our laboratory has significantly contributed over the years. We compile data from recent literature on the potential mechanisms driving fibrosis resolution such as MF' apoptosis, senescence, and reversal to quiescence. FUTURE DIRECTIONS We conclude with a brief description of how epigenetics, an evolving field, can regulate the behavior of MF and of how new "omics" tools may advance our understanding of the mechanisms by which the fibrogenic response to liver injury occurs.
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Affiliation(s)
- Elena Arriazu
- 1 Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine , New York, New York
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Epimorphin alters the inhibitory effects of SOX9 on Mmp13 in activated hepatic stellate cells. PLoS One 2014; 9:e100091. [PMID: 24971829 PMCID: PMC4074045 DOI: 10.1371/journal.pone.0100091] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 05/22/2014] [Indexed: 01/09/2023] Open
Abstract
Background and Aims Liver fibrosis is a major cause of morbidity and mortality. It is characterised by excessive extracellular matrix (ECM) deposition from activated hepatic stellate cells (HSCs). Although potentially reversible, treatment remains limited. Understanding how ECM influences the pathogenesis of the disease may provide insight into novel therapeutic targets for the disease. The extracellular protein Epimorphin (EPIM) has been implicated in tissue repair mechanisms in several tissues, partially, through its ability to manipulate proteases. In this study, we have identified that EPIM modulates the ECM environment produced by activated hepatic stellate cells (HSCs), in part, through down-regulation of pro-fibrotic Sex-determining region Y-box 9 (SOX9). Methods Influence of EPIM on ECM was investigated in cultured primary rat HSCs. Activated HSCs were treated with recombinant EPIM or SOX9 siRNA. Core fibrotic factors were evaluated by immunoblotting, qPCR and chromatin immunoprecipitation (ChIP). Results During HSC activation EPIM became significantly decreased in contrast to pro-fibrotic markers SOX9, Collagen type 1 (COL1), and α- Smooth muscle actin (α-SMA). Treatment of activated HSCs with recombinant EPIM caused a reduction in α-SMA, SOX9, COL1 and Osteopontin (OPN), while increasing expression of the collagenase matrix metalloproteinase 13 (MMP13). Sox9 abrogation in activated HSCs increased EPIM and MMP13 expression. Conclusion These data provide evidence for EPIM and SOX9 functioning by mutual negative feedback to regulate attributes of the quiescent or activated state of HSCs. Further understanding of EPIM's role may lead to opportunities to modulate SOX9 as a therapeutic avenue for liver fibrosis.
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da Costa AN, Plymoth A, Santos-Silva D, Ortiz-Cuaran S, Camey S, Guilloreau P, Sangrajrang S, Khuhaprema T, Mendy M, Lesi OA, Chang HK, Oh JK, Lee DH, Shin HR, Kirk GD, Merle P, Beretta L, Hainaut P. Osteopontin and latent-TGF β binding-protein 2 as potential diagnostic markers for HBV-related hepatocellular carcinoma. Int J Cancer 2014; 136:172-81. [PMID: 24803312 DOI: 10.1002/ijc.28953] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 04/17/2014] [Indexed: 12/12/2022]
Abstract
Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC.
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Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication. Clin Sci (Lond) 2014; 126:845-55. [PMID: 24438228 DOI: 10.1042/cs20130473] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C.
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Nagoshi S. Osteopontin: Versatile modulator of liver diseases. Hepatol Res 2014; 44:22-30. [PMID: 23701387 DOI: 10.1111/hepr.12166] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 05/12/2013] [Accepted: 05/16/2013] [Indexed: 12/16/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein, involved in pathological conditions including inflammation, immunity, angiogenesis, fibrosis and cancer progression in various tissues. Hepatic inflammation and fibrosis induced by feeding with a diet deficient in methionine and choline (MCD diet) were markedly attenuated in OPN knockout mice when compared with wild-type mice in the model of non-alcoholic steatohepatitis (NASH). Hepatic cholangiocytes, myofibroblastic stellate cells and natural killer T cells were suggested to secret OPN in mice fed an MCD diet. Plasma and hepatic OPN levels were significantly higher in patients with NASH with advanced fibrosis than in those with early fibrosis. Hepatic OPN mRNA level was correlated with hepatic neutrophil infiltration and fibrosis in patients with alcoholic liver diseases. In those with hepatocellular carcinoma (HCC), OPN levels in plasma and HCC were prognostic factors after liver resection or transplantation. Downregulation of OPN inhibited tumor growth and lung metastasis in nude mice implanted with HCC cells. The single nucleotide polymorphism in the promoter region of the OPN gene was shown to be associated with activity of hepatitis in chronic hepatitis C patients, prognosis in patients with HCC, and growth and lung metastasis of HCC xenografts in nude mice. OPN was reported to be a downstream effecter of Hedgehog pathway, which modulates hepatic fibrosis and carcinogenesis. This review focuses on the roles of OPN in hepatic inflammation, fibrosis and cancer progression. Further elucidation of cellular interactions and molecular mechanisms associated with OPN actions may contribute to development of novel strategies for treatment of the liver diseases.
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Affiliation(s)
- Sumiko Nagoshi
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
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Salem M, Atti SA, Raziky ME, Darweesh SK, Sharkawy ME. Clinical Significance of Plasma Osteopontin Level as a Biomarker of Hepatocellular Carcinoma. Gastroenterology Res 2013; 6:191-199. [PMID: 27785253 PMCID: PMC5051095 DOI: 10.4021/gr499w] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2012] [Indexed: 12/28/2022] Open
Abstract
Background Biomarkers of hepatocellular carcinoma (HCC) are helpful in screening, diagnosis and follow up of cases. Osteopontin (OPN) is a glycoprotein secreted by osteoblasts, osteoclasts, macrophages and T cells, and is over-expressed in a variety of tumors, including carcinomas of liver, stomach, breast, lung, colon, and prostate. So, the aim of this study was to verify the possibility of using the plasma Osteopontin level as a biomarker for diagnosis of HCC. Methods The study included 70 subjects divided into three groups: group I had 30 patients with HCC (proved by histopathology or combined spiral CT and elevated alpha-fetoprotein) on top of HCV, group II had 30 patients with HCV infection and group III had 10 healthy subjects serving as control. Osteopontin level was measured in plasma of the studied subjects by ELISA, serum alpha fetoprotein (AFP) level was also measured by EIA. Results Osteopontin levels were significantly elevated in patients with HCC and in HCV patients in comparison to control group (P: 0.005). There was significant correlation between OPN and AFP levels (P: 0.00). The sensitivity and specificity of OPN for selective detection of HCC group over the non-HCC group (HCV group and healthy control group) were73% and 54%, respectively, at a cut-off value of 128.5 ng/mL. Plasma OPN levels directly correlated with the tumor number but not with the size of the tumor (P: 0.00). Conclusion Plasma OPN level appears to be an additional biomarker for HCC detection.
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Affiliation(s)
- Mona Salem
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Sahar Abdel Atti
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Maisa El Raziky
- Tropical Medicine and Hepatology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Samar Kamal Darweesh
- Tropical Medicine and Hepatology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Marwa El Sharkawy
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
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Osteopontin contributes to TGF-β1 mediated hepatic stellate cell activation. Dig Dis Sci 2012; 57:2883-91. [PMID: 22661273 DOI: 10.1007/s10620-012-2248-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2011] [Accepted: 05/03/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND PURPOSE Liver fibrosis is characterized by accumulation of extracellular matrix. Our previous study found that osteopontin (OPN) increased in plasma of cirrhotic patients and indicative of cirrhosis staging. The present study was designed to investigate the expression of OPN in liver tissues and plasma of cirrhotic patients and further explore the role of OPN in human hepatic stellate cell (HSC) activation. METHODS We used immunohistochemical staining and enzyme-linked immunosorbent assay to evaluate the expression level of OPN in liver tissues and plasma from cirrhotic patients, respectively. We produced lentivirus particles and infected target cell to manipulate OPN expression. Infection efficiency was determined by real-time RT-PCR and western blot. Cell proliferation was determined using CCK8 assay, and phenotypes of HSC activation were determined by real-time RT-PCR. OPN promoter activity was determined by dual luciferase reporter assay. RESULTS We found that OPN expression in human cirrhotic liver tissues was upregulated compared to normal controls. In addition, its expression correlated with Child-Pugh classification, MELD score and the occurrence of complications. We further explored OPN level in patients' plasma and showed that its level correlated with transforming growth factor-β1 (TGF-β1). In human HSC cell line LX-2, we found that change of OPN expression level could not only affect the proliferation of cells but also the TGF-β1 mediated HSC activation. Moreover, OPN was increased by TGF-β1 stimulation and regulated by TGF-β1 at transcription level. CONCLUSIONS OPN is upregulated in liver tissues and plasma of cirrhotic patients and promotes TGF-β1 mediated HSC activation.
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Zhao L, Wang Y, Qu N, Huang C, Chen L. Significance of Plasma Osteopontin Levels in Patients with Bladder Urothelial Carcinomas. Mol Diagn Ther 2012; 16:311-6. [DOI: 10.1007/s40291-012-0005-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bertino G, Ardiri A, Malaguarnera M, Malaguarnera G, Bertino N, Calvagno GS. Hepatocellualar carcinoma serum markers. Semin Oncol 2012; 39:410-33. [PMID: 22846859 DOI: 10.1053/j.seminoncol.2012.05.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world. In most cases, HCC is diagnosed at a late stage. Therefore, the prognosis of patients with HCC is generally poor. The recommended screening strategy for patients with cirrhosis includes the determination of serum α-fetoprotein (AFP) levels and an abdominal ultrasound every 6 months to detect HCC at an earlier stage. AFP, however, is a marker characterized by poor sensitivity and specificity, and abdominal ultrasound is highly dependent on the operator's experience. In addition to AFP, Lens culinaris agglutinin-reactive AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), glypican-3 (GPC-3), osteopontin (OPN), and several other biomarkers (such as squamous cell carcinoma antigen-immunoglobulin M complexes [SCCA-IgM], alpha-1-fucosidase [AFU], chromogranin A [CgA], human hepatocyte growth factor, insulin-like growth factor) have been proposed as markers for the early detection of HCC. For these markers, we describe the mechanisms of production, and their diagnostic and prognosis roles. None of them is optimal; however, when used together, their sensitivity in detecting HCC is increased. Recent research has shown that some biomarkers have mitogenic and migratory activities in the angiogenesis of HCC and are a factor of tumor growth.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Medical and Pediatric Sciences, Policlinic of Catania, University of Catania, Catania, Italy.
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Pritchett J, Harvey E, Athwal V, Berry A, Rowe C, Oakley F, Moles A, Mann DA, Bobola N, Sharrocks AD, Thomson BJ, Zaitoun AM, Irving WL, Guha IN, Hanley NA, Hanley KP. Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. Hepatology 2012; 56:1108-16. [PMID: 22488688 PMCID: PMC3638324 DOI: 10.1002/hep.25758] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
UNLABELLED Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. CONCLUSION These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis.
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Affiliation(s)
- James Pritchett
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Emma Harvey
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Varinder Athwal
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Andrew Berry
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Cliff Rowe
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Fiona Oakley
- Liver Research Group, Institute of Cellular Medicine, University of NewcastleNewcastle-upon-Tyne, United Kingdom
| | - Anna Moles
- Liver Research Group, Institute of Cellular Medicine, University of NewcastleNewcastle-upon-Tyne, United Kingdom
| | - Derek A Mann
- Liver Research Group, Institute of Cellular Medicine, University of NewcastleNewcastle-upon-Tyne, United Kingdom
| | - Nicoletta Bobola
- School of Dentistry, University of ManchesterManchester, United Kingdom
| | - Andrew D Sharrocks
- Faculty of Life Sciences, University of ManchesterManchester, United Kingdom
| | - Brian J Thomson
- School of Molecular Medical Sciences, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center CampusNottingham United Kingdom
| | - Abed M Zaitoun
- Department of Cellular Pathology, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center CampusNottingham United Kingdom
| | - William L Irving
- School of Molecular Medical Sciences, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center CampusNottingham United Kingdom
| | - Indra N Guha
- Liver Unit, National Institute of Health Research, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center CampusNottingham United Kingdom
| | - Neil A Hanley
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
| | - Karen Piper Hanley
- Endocrinology and Diabetes Group, School of Biomedicine, University of ManchesterManchester, United Kingdom
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Cao DX, Li ZJ, Jiang XO, Lum YL, Khin E, Lee NP, Wu GH, Luk JM. Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers. World J Gastroenterol 2012; 18:3923-30. [PMID: 22912540 PMCID: PMC3419986 DOI: 10.3748/wjg.v18.i30.3923] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2012] [Revised: 05/11/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer and liver cancer are among the most common malignancies and the leading causes of death worldwide, due to late detection and high recurrence rates. Today, these cancers have a heavy socioeconomic burden, for which a full understanding of their pathophysiological features is warranted to search for promising biomarkers and therapeutic targets. Osteopontin (OPN) is overexpressed in most patients with gastric and liver cancers. Over the past decade, emerging evidence has revealed a correlation of OPN level and clinicopathological features and prognosis in gastric and liver cancers, indicating its potential as an independent prognostic indicator in such patients. Functional studies have verified the potential of OPN knockdown as a therapeutic approach in vitro and in vivo. Furthermore, OPN mediates multifaceted roles in the interaction between cancer cells and the tumor microenvironment, in which many details need further exploration. OPN signaling results in various functions, including prevention of apoptosis, modulation of angiogenesis, malfunction of tumor-associated macrophages, degradation of extracellular matrix, activation of phosphoinositide 3-kinase-Akt and nuclear factor-κB pathways, which lead to tumor formation and progression, particularly in gastric and liver cancers. This editorial aims to review recent findings on alteration in OPN expression and its clinicopathological associations with tumor progression, its potential as a therapeutic target, and putative mechanisms in gastric and liver cancers. Better understanding of the implications of OPN in tumorigenesis might facilitate development of therapeutic regimens to benefit patients with these deadly malignancies.
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Abstract
The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Brittany N Bohinc
- Department of Endocrinology, Diabetes and Metabolism, Duke University Hospital, Durham, NC 27710, USA
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Bassyouni IH, Bassyouni RH, Ibrahim NH, Soliman AF. Elevated serum osteopontin levels in chronic hepatitis C virus infection: association with autoimmune rheumatologic manifestations. J Clin Immunol 2012; 32:1262-9. [PMID: 22730056 DOI: 10.1007/s10875-012-9727-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 06/15/2012] [Indexed: 12/11/2022]
Abstract
Owing to the suggested role of osteopontin (OPN) in inflammation, autoimmunity and fibrosis, we investigated their serum concentrations in chronic hepatitis C virus (HCV) infected patients with and without autoimmune manifestations and correlated those levels to clinical manifestations and the histological severity of hepatic fibrosis. A total of 70 chronic HCV-infected patients (35 with and 35 without autoimmune rheumatic manifestations) were compared with 35 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. OPN serum levels were assessed by an Enzyme Linked Immunosorbant Assay. The mean serum OPN levels were higher in HCV patients with autoimmune rheumatologic manifestations and in patients without; than that for the normal controls (p = 0.000). The mean OPN values progressively increased by increasing severity of liver fibrosis (p = 0.009). Multivariate analysis revealed that the presence of rheumatologic manifestations had the highest predictive value (b = 7.141, Beta = 0.414, p = 0.000) followed by liver fibrosis (b = 4.522, Beta = 0.444, p = 0.000) on the variation of OPN levels in our HCV patients. Among the group of patients with HCV and rheumatologic involvement, OPN serum levels were higher in patients with positive cryoglobulin and rheumatoid factor than in those without, and with systemic vasculitis than in those without. Correlation analysis didn't reveal any statistical significance of OPN with age, serum albumin, aminotransferases and viral load. Our data suggests OPN as a promising marker for HCV associated autoimmune rheumatologic involvement, particularly with regard to development of vasculitis and cryoglobinemia. In addition, it could serve as a biomarker to evaluate the severity of liver damages in HCV infected subjects.
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Affiliation(s)
- Iman H Bassyouni
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt, 12613.
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The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One 2012; 7:e35612. [PMID: 22530059 PMCID: PMC3329460 DOI: 10.1371/journal.pone.0035612] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 03/18/2012] [Indexed: 12/11/2022] Open
Abstract
Background Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis. Methodology/Principal Findings OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFβ expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F≥2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F≥2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury. Conclusion/Significance OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.
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Ke HL, Chang LL, Yang SF, Lin HH, Li CC, Wu DC, Wu WJ. Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma. Urol Oncol 2011; 29:703-9. [DOI: 10.1016/j.urolonc.2009.10.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Revised: 10/15/2009] [Accepted: 10/15/2009] [Indexed: 12/31/2022]
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Response: Osteopontin Levels in Patients with Hepatitis C Virus-related Hepatocellular Carcinoma. Arch Med Res 2011. [DOI: 10.1016/j.arcmed.2011.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Association of circulating osteopontin levels with clinical outcomes in postoperative biliary atresia. Pediatr Surg Int 2011; 27:283-8. [PMID: 21046114 DOI: 10.1007/s00383-010-2799-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/30/2009] [Indexed: 12/16/2022]
Abstract
PURPOSE Biliary atresia (BA) is one of the most serious liver disorders in children. The aims of the present study were to investigate circulating levels of osteopontin in BA children compared with healthy controls and to evaluate the relationship between circulating osteopontin and therapeutic outcome of BA patients. METHODS Fifty-nine BA patients post-Kasai operation and 13 healthy children were recruited. The patients were divided into two groups according to their serum total bilirubin levels (TB < 2, jaundice-free vs. TB ≥ 2 mg/dL, persistent jaundice) and alanine aminotransferase (ALT < 45, normal ALT vs. ALT ≥ 45 IU/L, elevated ALT). Plasma osteopontin levels were analyzed using commercial enzyme-linked immunosorbent assay. RESULTS The circulating osteopontin was higher in BA children compared with that of healthy controls (146.9 ± 19.1 vs. 28.0 ± 8.4 ng/mL, P = 0.001). The BA patients with persistent jaundice had more increased plasma osteopontin levels than those without jaundice (157.8 ± 47.9 vs. 27.5 ± 6.4 ng/mL, P = 0.001). Furthermore, plasma osteopontin levels in BA patients with elevated ALT were significantly higher than those with normal ALT (103.2 ± 29.2 vs. 24.5 ± 7.9 ng/mL, P = 0.01). In addition, circulating osteopontin was positively correlated with serum total bilirubin (r = 0.526, P < 0.001) and with serum ALT (r = 0.575, P < 0.001). Subsequent analysis showed that the BA patients with portal hypertension had more elevated plasma osteopontin compared to those without portal hypertension (116.7 ± 31.1 vs. 19.5 ± 9.3 ng/mL, P = 0.01). CONCLUSION Increased circulating osteopontin was associated with the development of hepatic dysfunction and portal hypertension in BA patients. Circulating osteopontin may serve as a possible marker reflecting disease severity and monitoring the disease progression in postoperative BA patients.
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Machado MV, Cortez-Pinto H. Osteopontin: a missing link between hedgehog signaling and fibrosis in nonalcoholic steatohepatitis. Hepatology 2011; 53:382-4. [PMID: 21274859 DOI: 10.1002/hep.24118] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Honsawek S, Chayanupatkul M, Chongsrisawat V, Vejchapipat P, Poovorawan Y. Increased osteopontin and liver stiffness measurement by transient elastography in biliary atresia. World J Gastroenterol 2010; 16:5467-73. [PMID: 21086566 PMCID: PMC2988241 DOI: 10.3748/wjg.v16.i43.5467] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze plasma osteopontin levels and liver stiffness using transient elastography in postoperative biliary atresia (BA) children compared with healthy controls.
METHODS: Thirty children with postoperative BA and 10 normal controls were enrolled. The patients were categorized into two groups according to their jaundice status. Plasma levels of osteopontin were determined using commercially available enzyme-linked immunosorbent assay. Liver stiffness was measured by using transient elastography (Fibroscan). Ten validated Fibroscan measurements were performed in each patient and control with the result expressed in kilopascals (kPa).
RESULTS: Plasma osteopontin was significantly elevated in BA children compared with that of healthy controls (47.0 ± 56.4 ng/mL vs 15.1 ± 15.0 ng/mL, P = 0.01). The liver stiffness measurement was markedly elevated in the patients with BA compared with that of controls (26.9 ± 24.6 kPa vs 3.9 ± 0.7 kPa, P = 0.001). Subgroup analysis showed that the BA patients with jaundice had more pronounced plasma osteopontin levels than those without jaundice (87.1 ± 61.6 ng/mL vs 11.9 ± 6.1 ng/mL, P = 0.001). Furthermore, the mean liver stiffness was significantly greater in the jaundiced BA patients compared with non-jaundiced patients (47.7 ± 21.8 kPa vs 8.7 ± 3.0 kPa, P = 0.001). Additionally, plasma osteopontin was positively related to serum total bilirubin (r = 0.64, P < 0.001). There was also a correlation between plasma osteopontin and liver stiffness values (r = 0.60, P < 0.001).
CONCLUSION: High plasma osteopontin positively correlated with degree of hepatic fibrosis and could be used as a biochemical parameter reflecting disease severity in postoperative BA children.
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