Liraglutide Inhibits the Apoptosis of MC3T3-E1 Cells Induced by Serum Deprivation through cAMP/PKA/β-Catenin and PI3K/AKT/GSK3β Signaling Pathways
Xuelun Wu1,2, Shilun Li2, Peng Xue1,2, and Yukun Li1,2,*
1Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, PR China, 2Key Orthopaedic Biomechanics Laboratory of Hebei Province, Shijiazhuang 050051, Hebei Province, PR China
Received December 2, 2017; Revised December 28, 2017; Accepted December 29, 2017.; Published online February 21, 2018.
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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 βcatenin phosphorylation at Ser675 cite 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 liraglutideinduced 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. 
Keywords: apoptosis, liraglutide, osteoblast, signaling pathway 

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28 February 2018 Volume 41,
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