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Title: Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin

Abstract

Previous studies have proven that glucagon-like peptide-1 (GLP-1) and its receptor agonist exert favorable anabolic effects on skeletal metabolism. However, whether GLP-1 could directly impact osteoblast-mediated bone formation is still controversial, and the underlying molecular mechanism remains to be elucidated. Thus in this paper, we investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on murine MC3T3-E1 preosteoblasts proliferation and differentiation and explored the potential cellular basis. Our study confirmed the presence of GLP-1R in MC3T3-E1, and demonstrated that liraglutide promotes osteoblasts proliferation at an intermediate concentration (100 nM) and time (48 h), upregulated the expression of osteoblastogenic biomarkers at various stages, and stimulated osteoblastic mineralization. Liraglutide also elevated the intracellular cAMP level and phosphorylation of AKT, ERK and β-catenin simultaneously with increased nuclear β-catenin content and transcriptional activity. Pretreatment of cells with the inhibitors LY294002, PD98059, H89 and GLP-1R and β-catenin siRNA partially blocked the liraglutide-induced signaling activation and attenuated the facilitating effect of liraglutide on MC3T3-E1 cells. Collectively, liraglutide was capable of acting upon osteoblasts directly through GLP-1R by activating PI3K/AKT, ERK1/2, cAMP/PKA/β-cat-Ser675 signaling to promote bone formation via GLP-1R. Thus, GLP-1 analogues may be potential therapeutic strategy for the treatment of osteoporosis in diabetics. -more » Highlights: • Liraglutide promoted proliferation and differentiation of murine MC3T3-E1 preosteoblasts. • GLP-1R was expressed in MC3T3-E1 cells. • These effects were mediated by PI3K/AKT, ERK1/2, and cAMP/PKA pathway via GLP-1R. • β-catenin was also involved in this complex process.« less

Authors:
 [1];  [2];  [3];  [1];  [2];  [1];  [2]
  1. Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province (China)
  2. (China)
  3. Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province (China)
Publication Date:
OSTI Identifier:
22738186
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 360; Journal Issue: 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMP; BIOLOGICAL MARKERS; CONNECTIVE TISSUE CELLS; GLUCAGON; PHOSPHOTRANSFERASES; RECEPTORS; SIGNALS

Citation Formats

Wu, Xuelun, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Shilun, Xue, Peng, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Yukun, and Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province. Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.09.018.
Wu, Xuelun, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Shilun, Xue, Peng, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Yukun, & Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province. Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin. United States. doi:10.1016/J.YEXCR.2017.09.018.
Wu, Xuelun, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Shilun, Xue, Peng, Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, Li, Yukun, and Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province. Wed . "Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin". United States. doi:10.1016/J.YEXCR.2017.09.018.
@article{osti_22738186,
title = {Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin},
author = {Wu, Xuelun and Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province and Li, Shilun and Xue, Peng and Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province and Li, Yukun and Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province},
abstractNote = {Previous studies have proven that glucagon-like peptide-1 (GLP-1) and its receptor agonist exert favorable anabolic effects on skeletal metabolism. However, whether GLP-1 could directly impact osteoblast-mediated bone formation is still controversial, and the underlying molecular mechanism remains to be elucidated. Thus in this paper, we investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on murine MC3T3-E1 preosteoblasts proliferation and differentiation and explored the potential cellular basis. Our study confirmed the presence of GLP-1R in MC3T3-E1, and demonstrated that liraglutide promotes osteoblasts proliferation at an intermediate concentration (100 nM) and time (48 h), upregulated the expression of osteoblastogenic biomarkers at various stages, and stimulated osteoblastic mineralization. Liraglutide also elevated the intracellular cAMP level and phosphorylation of AKT, ERK and β-catenin simultaneously with increased nuclear β-catenin content and transcriptional activity. Pretreatment of cells with the inhibitors LY294002, PD98059, H89 and GLP-1R and β-catenin siRNA partially blocked the liraglutide-induced signaling activation and attenuated the facilitating effect of liraglutide on MC3T3-E1 cells. Collectively, liraglutide was capable of acting upon osteoblasts directly through GLP-1R by activating PI3K/AKT, ERK1/2, cAMP/PKA/β-cat-Ser675 signaling to promote bone formation via GLP-1R. Thus, GLP-1 analogues may be potential therapeutic strategy for the treatment of osteoporosis in diabetics. - Highlights: • Liraglutide promoted proliferation and differentiation of murine MC3T3-E1 preosteoblasts. • GLP-1R was expressed in MC3T3-E1 cells. • These effects were mediated by PI3K/AKT, ERK1/2, and cAMP/PKA pathway via GLP-1R. • β-catenin was also involved in this complex process.},
doi = {10.1016/J.YEXCR.2017.09.018},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 360,
place = {United States},
year = {2017},
month = {11}
}