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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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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          Osteoporosis: now and the future.

          Tilman Rachner, Sundeep Khosla, Lorenz Hofbauer (2011)
          Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Regulation of bone mass by Wnt signaling.

            Venkatesh Krishnan, Henry Bryant, Ormond A Macdougald (2006)
            Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass. Of the pathways activated by Wnts, it is signaling through the canonical (i.e., Wnt/beta-catenin) pathway that increases bone mass through a number of mechanisms including renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis. This pathway is an enticing target for developing drugs to battle skeletal diseases as Wnt/beta-catenin signaling is composed of a series of molecular interactions that offer potential places for pharmacological intervention. In considering opportunities for anabolic drug discovery in this area, one must consider multiple factors, including (a) the roles of Wnt signaling for development, remodeling, and pathology of bone; (b) how pharmacological interventions that target this pathway may specifically treat osteoporosis and other aspects of skeletal health; and (c) whether the targets within this pathway are amenable to drug intervention. In this Review we discuss the current understanding of this pathway in terms of bone biology and assess whether targeting this pathway might yield novel therapeutics to treat typical bone disorders.
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              Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration.

              Dongsu Park, Joel A. Spencer, Bong Ihn Koh … (2012)
              Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered clinical application despite little definition of their function in residence. Here, we report genetic pulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiring replenishment from bone-marrow-derived, Mx1(+) stromal cells with "MSC" features. These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Single cell transplantation yielded progeny that both preserve progenitor function and differentiate into osteoblasts, producing new bone. They are capable of local and systemic translocation and serial transplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineage restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be a heterogeneous population with the Mx1(+) population, representing a highly dynamic and stress responsive stem/progenitor cell population of fate-restricted potential that feeds the high cell replacement demands of the adult skeleton. Copyright © 2012 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 231 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaoxing Luo
                Journal
                Journal ID (nlm-ta): Stem Cell Reports
                Journal ID (iso-abbrev): Stem Cell Reports
                Title: Stem Cell Reports
                Publisher: Elsevier
                ISSN (Electronic): 2213-6711
                Publication date PMC-release: 03 March 2016
                Publication date Collection: 12 April 2016
                Publication date (Electronic): 03 March 2016
                Volume: 6
                Issue: 4
                Pages: 579-591
                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

                Article
                Publisher ID: S2213-6711(16)00035-7
                DOI: 10.1016/j.stemcr.2016.02.002
                PMC ID: 4834036
                PubMed ID: 26947974
                SO-VID: 04984507-cd55-455c-92f2-0bc3e5f0030b
                Copyright © © 2016 The Authors
                License:

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

                History
                Date received : 24 August 2015
                Date revision received : 30 January 2016
                Date accepted : 1 February 2016
                Categories
                Subject: Article

                Keywords: exendin-4,glucagon-like peptide 1 receptor,bone marrow stromal cells,osteoblast,osteoporosis
                Data availability:
                Keywords: exendin-4, glucagon-like peptide 1 receptor, bone marrow stromal cells, osteoblast, osteoporosis

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