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Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-? (TGF-?) superfamily and are important regulators in IPF. Here we identified BMP endothelial cell precursor-derived regulator (BMPER) as a key regulator of fibroblast activation. BMPER is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-?/BMP signaling, but its role in lung fibrosis is not clear. BMPER is highly expressed in human IPF lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased BMPER expression in fibroblasts, and attenuated the invasion and migration of IPF lung fibroblasts. Furthermore, siRNA-mediated reduction of BMPER in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated BMPER expression and reduced lung fibrosis in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for IPF by modulating fibroblast activation.

SUBMITTER: Huan C

PROVIDER: S-EPMC4595647 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo.

Huan Caijuan C Yang Ting T Liang Jiurong J Xie Ting T Cheng Luis L Liu Ningshan N Kurkciyan Adrianne A Monterrosa Mena Jessica J Wang Chen C Dai Huaping H Noble Paul W PW Jiang Dianhua D

Scientific reports 20151007

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily and are important regulators in IPF. Here we identified BMP endothelial cell precursor-derived regulator (BMPER) as a key regulator of fibroblast activation. BMPER is a secreted ...[more]

PMID: 26442443

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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-?1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition.To identify the mechanism of Arsenic trioxide's (ATO)'s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-?1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as ?-smooth muscle actin (?-SMA) and ?-1 type I collagen.Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-?1-induced ?-smooth muscle actin (?-SMA) and ?-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-?1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-?1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-?1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung ?-1 type I collagen mRNA and protein expression.In summary, these data indicate that low concentrations of ATO inhibit TGF-?1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.

Dataset Information

Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo.

Publications

Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo.

Similar Datasets

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