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Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

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      Summary

      Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis.

      Highlights

      • GLP-1 receptor agonist exendin-4 improved unloading-induced bone loss
      • Activation of GLP-1 receptor enhanced BMSC osteogenic differentiation
      • Activation of GLP-1 receptor inhibited BMSC adipogenic differentiation
      • Exendin-4 promoted bone formation and increased bone mass through β-catenin

      Abstract

      In this article, Luo and colleagues show that GLP-1 receptor agonist exendin-4 (Ex-4) increased bone mass in rat unloading-induced osteoporosis. Ex-4 promoted BMSC osteogenic differentiation and inhibited their adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provides a molecular basis for GLP-1 therapeutic potential against osteoporosis.

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      Most cited references 38

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      Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
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          The physiology of glucagon-like peptide 1.

          Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.
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            Author and article information

            Affiliations
            [1 ]Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
            [2 ]Institute of Orthopaedics & Traumatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
            [3 ]Department of Aerospace Physiology, Fourth Military Medical University, Xi'an 710032, China
            [4 ]Department of Pharmacy, Kunming General Hospital of Chengdu Military Region, Kunming 650032, China
            Author notes
            []Corresponding author xxluo3@ 123456fmmu.edu.cn
            [5]

            Co-first author

            [6]

            Co-senior author

            Contributors
            Journal
            Stem Cell Reports
            Stem Cell Reports
            Stem Cell Reports
            Elsevier
            2213-6711
            03 March 2016
            12 April 2016
            03 March 2016
            : 6
            : 4
            : 579-591
            26947974
            4834036
            S2213-6711(16)00035-7
            10.1016/j.stemcr.2016.02.002
            © 2016 The Authors

            This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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