Osteopontin induces ductular reaction contributing to liver fibrosis

Wang, Xiaodong; Lopategi, Aritz; Ge, Xiaodong; Lu, Yongke; Kitamura, Naoto; Urtasun, Raquel; Leung, Tung Ming; Fiel, M. Isabel; Nieto, Natalia

doi:10.1136/gutjnl-2013-306373

Cited by 97 publications

(121 citation statements)

References 46 publications

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“…Indeed, TGF-βs impair hepatocyte lineage differentiation, promote cholangiocyte lineage differentiation (42,46), and increase EMT (30). Because SPP1 (osteopontin) produced by cholangiocytes also drives inflammatory cell infiltration, fibrosis, and cholangiocyte differentiation (47), some Mob1a/1b-deficient liver phenotypes may depend in part on SPP1 overexpression.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Nishio

Sugimachi

Goto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

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Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

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Section: Discussionmentioning

confidence: 99%

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Nishio

Sugimachi

Goto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

160

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“…Wang et al (26) identified a role of OPN in HPC activation, and demonstrated that HPC-driven ductular reaction was a critical mechanism underlying the progression of liver fibrosis. Another study demonstrated that OPN neutralization suppressed liver fibrosis in mice (27).…”

Section: Discussionmentioning

confidence: 99%

Serum osteopontin is a predictor of prognosis for HBV‑associated acute‑on‑chronic liver failure

Liu

et al. 2017

biom rep

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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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“…Local expertise and personal experience with the model is likely to be an important factor when planning an experiment with TAA. Here we present our experience with the TAA model, which includes chronic oral exposure in C57BL/6 mice at a fixed dose (300 mg/L in drinking water) for 2-4 months, 13 IP injection of TAA in Sprague-Dawley rats for 11 weeks with or without an experimental drug, 14 and a time-course pilot study of TAA by IP injection in Sprague-Dawley rats for 12 weeks (Figure 1). We report the rate and degree of fibrosis and cirrhosis development, changes in portal pressures and liver collagen content, as well as the mortality rate in the experimental animals.…”

Section: Historical Background and Current Usagementioning

confidence: 99%

“…Our experience with orally administered TAA was recently published 13 and is summarized below as a standard for reference:…”

Section: Taa Via Oral Administrationmentioning

confidence: 99%

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

et al. 2015

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In addition to carbon tetrachloride (CCl 4 ), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl 4 , TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis.

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Osteopontin induces ductular reaction contributing to liver fibrosis

Abstract: OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-β.

Cited by 97 publications

References 46 publications

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Serum osteopontin is a predictor of prognosis for HBV‑associated acute‑on‑chronic liver failure

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

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