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首页> 外文期刊>Molecules and cells >Liraglutide Inhibits the Apoptosis of MC3T3-E1 Cells Induced by Serum Deprivation through cAMP/PKA/β-Catenin and PI3K/AKT/GSK3β Signaling Pathways
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Liraglutide Inhibits the Apoptosis of MC3T3-E1 Cells Induced by Serum Deprivation through cAMP/PKA/β-Catenin and PI3K/AKT/GSK3β Signaling Pathways

机译：利拉鲁肽通过cAMP / PKA /β-Catenin和PI3K / AKT /GSK3β信号通路抑制血清剥夺诱导的MC3T3-E1细胞凋亡

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In recent years, the interest towards the relationship between incretins and bone has been increasing. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) and its receptor agonists exert beneficial anabolic influence on skeletal metabolism, such as promoting proliferation and differentiation of osteoblasts via entero-osseous-axis. However, little is known regarding the effects of GLP-1 on osteoblast apoptosis and the underlying mechanisms involved. Thus, in the present study, we investigated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist, on apoptosis of murine MC3T3-E1 osteoblastic cells. We confirmed the presence of GLP-1 receptor (GLP-1R) in MC3T3-E1 cells. Our data demonstrated that liraglutide inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as detected by Annexin V/PI and Hoechst 33258 staining and ELISA assays. Moreover, liraglutide upregulated Bcl-2 expression and downregulated Bax expression and caspase-3 activity at intermediate concentration (100 nM) for maximum effect. Further study suggested that liraglutide stimulated the phosphorylation of AKT and enhanced cAMP level, along with decreased phosphorylation of GSK3β, increased β-catenin phosphorylation at Ser675 site and upregulated nuclear β-catenin content and transcriptional activity. Pretreatment of cells with the PI3K inhibitor LY294002, PKA inhibitor H89, and siRNAs GLP-1R, β-catenin abrogated the liraglutide-induced activation of cAMP, AKT, β-catenin, respectively. In conclusion, these findings illustrate that activation of GLP-1 receptor by liraglutide inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation through cAMP/PKA/β-catenin and PI3K/Akt/GSK3β signaling pathways.
机译：近年来，对肠降血糖素与骨骼之间关系的兴趣不断增加。先前的研究表明，胰高血糖素样肽1（GLP-1）及其受体激动剂对骨骼代谢产生有益的合成代谢影响，例如通过肠骨轴促进成骨细胞的增殖和分化。但是，关于GLP-1对成骨细胞凋亡及其相关机制的了解还很少。因此，在本研究中，我们研究了胰高血糖素样肽1受体激动剂利拉鲁肽对鼠MC3T3-E1成骨细胞凋亡的影响。我们证实了MC3T3-E1细胞中存在GLP-1受体（GLP-1R）。我们的数据证明，如膜联蛋白V / PI和Hoechst 33258染色及ELISA分析所检测，利拉鲁肽抑制血清剥夺诱导的成骨细胞MC3T3-E1细胞凋亡。此外，利拉鲁肽在中等浓度（100 nM）上调Bcl-2表达，下调Bax表达和caspase-3活性，以发挥最大作用。进一步的研究表明，利拉鲁肽可刺激AKT的磷酸化并提高cAMP水平，同时降低GSK3β的磷酸化，增加Ser675位点的β-catenin磷酸化，并上调细胞核β-catenin的含量和转录活性。用PI3K抑制剂LY294002，PKA抑制剂H89和siRNA GLP-1R预处理细胞，β-catenin分别消除了利拉鲁肽诱导的cAMP，AKT，β-catenin激活。总之，这些发现表明利拉鲁肽对GLP-1受体的激活抑制了通过cAMP / PKA /β-catenin和PI3K / Akt /GSK3β信号通路引起的血清剥夺诱导的成骨MC3T3-E1细胞凋亡。

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