siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-induced hepatic fibrosis in rats

George, Joseph; Tsutsumi, Mikihiro

doi:10.1038/sj.gt.3302929

Cited by 115 publications

(109 citation statements)

References 43 publications

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“…Previous studies have suggested the implications of CTGF in the pathogenesis of hepatic fibrosis characterized by deposition of fibrillar collagens in the liver 21, 44, 45, 46. The full‐length CTGF molecule comprises four structural domains, that is modules 1–4, which are susceptible to proteolysis by hepatic stellate cells, yielding C‐terminal fragments composed of the modules 3 and 4 or the module 4 alone 46.…”

Section: Discussionmentioning

confidence: 99%

“…Stellate cells were isolated from about one year old albino rats and cultured as reported before 21. The cells were cultured in 50:50 mixture of DMEM and Ham's F12 medium (Invitrogen) containing 10% foetal bovine serum (FBS; Invitrogen) and antibiotics (100 units of penicillin G and 100 μg of streptomycin/ml of culture media) in a humidified incubator containing 5% CO 2 on air at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…CTGF plays a central role in the pathogenesis of hepatic fibrosis by triggering activation and transformation of quiescent hepatic stellate cells into myofibroblasts, and it also stimulates the production of CTGF itself 21, 22. Activated stellate cells over‐produce collagens, fibronectin and laminin under stimulation with CTGF 23.…”

Section: Introductionmentioning

confidence: 99%

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MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

George

Tsutsumi

Tsuchishima

2017

J Cellular Molecular Medi

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Connective tissue growth factor (CTGF) is involved in inflammation, pathogenesis and progression of liver fibrosis. Matrix metalloproteinase‐13 (MMP‐13) cleaves CTGF and releases several fragments, which are more potent than the parent molecule to induce fibrosis. The current study was aimed to elucidate the significance of MMP‐13 and CTGF and their downstream effects in liver injury and fibrosis. Hepatic fibrosis was induced using intraperitoneal injections of N‐nitrosodimethylamine (NDMA) in doses of 10 μg/g body weight on three consecutive days of each week over a period of 4 weeks in both wild‐type (WT) and MMP‐13 knockout mice. Administration of NDMA resulted in marked elevation of AST, ALT, TGF‐β1 and hyaluronic acid in the serum and activation of stellate cells, massive necrosis, deposition of collagen fibres and increase in total collagen in the liver of WT mice with a significant decrease in MMP‐13 knockout mice. Protein and mRNA levels of CTGF, TGF‐β1, α‐SMA and type I collagen and the levels of MMP‐2, MMP‐9 and cleaved products of CTGF were markedly increased in NDMA‐treated WT mice compared to the MMP‐13 knockout mice. Blocking of MMP‐13 with CL‐82198 in hepatic stellate cell cultures resulted in marked decrease of the staining intensity of CTGF as well as protein levels of full‐length CTGF and its C‐terminal fragments and active TGF‐β1. The data demonstrate that MMP‐13 and CTGF play a crucial role in modulation of fibrogenic mediators and promote hepatic fibrogenesis. Furthermore, the study suggests that blocking of MMP‐13 and CTGF has potential therapeutic implications to arrest liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

George

Tsutsumi

Tsuchishima

2017

J Cellular Molecular Medi

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“…Thus, it is a more specific target, and blocking it may reverse fibrosis and herald a new era in the treatment of fibrotic diseases. George and Tsutsumi (2007) used CTGF siRNA in N-nitrosodimethylamine-induced mice liver fibrosis models, and discovered that CTGF and TGF-β1 expression levels were significantly reduced, and connective tissue protein deposition in the liver was also reduced, suggesting that CTGF siRNA is a potential treatment for liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Expression of transforming growth factor-β1 and connective tissue growth factor in congenital biliary atresia and neonatal hepatitis liver tissue

Zhao

Peng

et al. 2016

Genet. Mol. Res.

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“…CTGF is implicated in the development of fibrosis in a variety of pathological scenarios, acting downstream of TGFb. 14 CTGF has previously been shown to be expressed by tenocytes, 15 and undergoes upregulation following injury. 16 CTGF has also been proposed as an attractive target to decrease scarring following tendon injury.…”

Section: Gene Expression Changes Mediated By Mast Cell Degranulationmentioning

confidence: 99%

Sodium cromolyn reduces expression of CTGF, ADAMTS1, and TIMP3 and modulates post‐injury patellar tendon morphology

Sharma

Abraham

Sampaio

et al. 2010

Journal Orthopaedic Research

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The purpose of this study was to determine whether administration of a mast cell inhibitor (sodium cromolyn, SC) would influence tendon repair and extracellular matrix gene expression following acute injury. CD1 mouse patellar tendons were unilaterally injured and mast cell prevalence was determined. The effect of SC injection on tendon hypercellularity, cross-sectional area, collagen organization, and expression of extracellular matrix-related genes was examined. Mast cell prevalence was markedly increased in injured patellar tendons ( p ¼ 0.009), especially at 8 weeks post-injury ( p ¼ 0.025). SC injection increased collagen organization compared to uninjected animals at 4 weeks and attenuated the development of tendon hypercellularity and tendon thickening post-injury. Expression of CTGF, ADAMTS1, and TIMP3 in injured tendon was reduced in the SC group. SC injections moderated the structural alterations of healing tendon in association with downregulation of several genes associated with tendon fibrosis. This work corroborates previous findings pointing to a role of mast cells in tendon repair. ß

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siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-induced hepatic fibrosis in rats

Cited by 115 publications

References 43 publications

MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

Expression of transforming growth factor-β1 and connective tissue growth factor in congenital biliary atresia and neonatal hepatitis liver tissue

Sodium cromolyn reduces expression of CTGF, ADAMTS1, and TIMP3 and modulates post‐injury patellar tendon morphology

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