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首页> 外文期刊>Cell biology international. >High-mobility group box-B1 (HMGB1) mediates the hypoxia-induced mesenchymal transition of osteoblast cells via activating ERK/JNK signaling
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High-mobility group box-B1 (HMGB1) mediates the hypoxia-induced mesenchymal transition of osteoblast cells via activating ERK/JNK signaling

机译：高迁移率族box-B1（HMGB1）通过激活ERK / JNK信号传导介导缺氧诱导的成骨细胞间质转化

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High-mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 activates monocytes and neutrophils, which are involved in inflammation during wounding. In this study, we investigated the promotion of HMGB1 under hypoxia and determined the regulatory role of HMGB1 on the fibrosis of mouse osteoblast-like MC3T3-E1 cells or of human osteoblast MG-63 cells. Results demonstrated that HMGB1 expression was significantly upregulated in MC3T3-E1 or MG-63 cells under hypoxia. We also found that treatment with 10 and 100 ng/mL of HMGB1 significantly promoted the fibrosis-associated markers such as Collagen I, a-SMA, whereas downregulated the E-cadherin, indicating the differentiation of MC3T3-E1 or MG-63 cells into fibroblast cells. Further investigation indicated that the HMGB1 treatment markedly activated the mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF)-kappa B nuclear translocation. On the other side, using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-kappa B all inhibited HMGB1-induced cellular differentiation and migration of MC3T3-E1 cells. In addition, knocking down of advanced glycation end products (RAGE) but not Toll-like receptor (TLR) 2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced the fibrosis of osteoblasts in vitro via activating the RAGE-MAPK and NF-kappa B interaction signaling pathways.
机译：高迁移率族盒1（HMGB1）是一种核蛋白，涉及与DNA的结合并影响染色质的调控和转录。 HMGB1激活单核细胞和嗜中性粒细胞，它们在受伤过程中与炎症有关。在这项研究中，我们调查了缺氧条件下HMGB1的促进作用，并确定了HMGB1对小鼠成骨细胞样MC3T3-E1细胞或人成骨细胞MG-63细胞纤维化的调节作用。结果表明，在缺氧条件下，MC3T3-E1或MG-63细胞中HMGB1的表达明显上调。我们还发现，以10 ng / mL和100 ng / mL的HMGB1处理可显着促进与纤维化相关的标志物，例如胶原I，a-SMA，而下调E-钙粘蛋白，表明MC3T3-E1或MG-63细胞分化为成纤维细胞。进一步的研究表明，HMGB1处理可显着激活丝裂原激活的蛋白激酶（MAPK），包括细胞外信号相关激酶（ERK），c-Jun N端激酶（JNK）和p38丝裂原激活的蛋白激酶（p38）磷酸化以及核因子（NF）-κB核易位。另一方面，使用蛋白激酶的特异性抑制剂和shRNA，我们观察到ERK，JNK，p38和NF-κB的阻遏均抑制HMGB1诱导的MC3T3-E1细胞分化和迁移。此外，shRNA敲低高级糖基化终产物（RAGE）而不是Toll样受体（TLR）2和TLR4，可减弱HMGB1诱导的成纤维细胞分化和迁移。总之，我们的研究表明，HMGB1通过激活RAGE-MAPK和NF-κB相互作用的信号传导通路在体外诱导成骨细胞纤维化。

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