2. Academic Validation
  3. Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway

Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway

  • Stem Cell Res Ther. 2018 Mar 9;9(1):57. doi: 10.1186/s13287-018-0771-y.
Banjun Ruan 1,  Zheng Zhu 2,  Zhao Yan 3,  Wei Yang 4,  Dongsheng Zhai 1,  Li Wang 1,  Zichen Ye 1,  Huanyu Lu 5,  An Xiang 1,  Jingwei Liang 6,  Yinghao Jiang 1,  Chengming Xu 1,  Zhenyu Wang 1,  Ming Wei 7,  Xiaoying Lei 1,  Xiaorui Cao 8,  Zifan Lu 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
  • 2 Institute of Urinary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
  • 3 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
  • 4 Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
  • 5 Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
  • 6 School of Pharmacy, China Medical University, Liaoning, 110122, China.
  • 7 Department of Pharmacology, Xi'an Medical University, Xi'an, 710021, People's Republic of China.
  • 8 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, People's Republic of China. [email protected].
  • 9 State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, 710032, People's Republic of China. [email protected].
PMID: 29523188 DOI: 10.1186/s13287-018-0771-y
Abstract

Background: The reciprocal fate decision of mesenchymal stem cells (MSCs) to either bone or adipocytes is determined by Wnt-related signaling and the glucagon-like peptide-1 receptor (GLP-1R). Azoramide, an ER stress alleviator, was reported to have an antidiabetic effect. In this study, we investigated the function of azoramide in regulating the lineage determination of MSCs for either adipogenic or osteogenic differentiation.

Methods: In this study, microcomputed tomography and histological analysis on bone morphogenetic protein (BMP)2-induced parietal periosteum bone formation assays, C3H10T1/2 and mouse bone marrow MSC-derived bone formation and adipogenesis assays, and specific staining for bone tissue and lipid droplets were used to evaluate the role of azoramide on the lineage determination of MSC differentiation. Cells were harvested for Western blot and quantitative real-time polymerase chain reaction (PCR), and immunofluorescence staining was used to explore the potential mechanism of azoramide for regulating MSC differentiation.

Results: Based on MSC-derived bone formation assays both in vivo and in vitro, azoramide treatment displayed a cell fate determining ability in favor of adipogenesis over osteogenesis. Further mechanistic characterizations disclosed that both the GLP-1R agonist peptide exendin-4 (Ex-4) and GLP-1R small interfering (si)RNA abrogated azoramide dual effects. Moreover, cAMP-protein kinase A (PKA)-mediated nuclear β-catenin activity was responsible for the negative function of azoramide on bone formation in favor of adipogenesis.

Conclusions: These data provide the first evidence to show that azoramide may serve as an antagonist against GLP-1R in MSC lineage determination.

Keywords

Adipogenesis; Azoramide; Glucagon-like peptide-1 receptor; MSC; Osteogenesis; Wnt.

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