title: Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice.
abstract: Some anti-diabetic therapies can have adverse effects on bone health and increase fracture risk. In this study, we tested the skeletal effects of chronic administration of two Glucagon-like peptide-1 receptor agonists (GLP-1RA), increasingly used for type 2 diabetes treatment, in a model of osteoporosis associated bone loss and examined the expression and activation of GLP-1R in bone cells. Mice were ovariectomised (OVX) to induce bone loss and four weeks later they were treated with Liraglutide (LIR) 0.3mg/kg/day, Exenatide (Ex-4) 10 μg/kg/day or saline for four weeks. Mice were injected with calcein and alizarin red prior to euthanasia, to label bone-mineralising surfaces. Tibial micro-architecture was determined by micro-CT and bone formation and resorption parameters measured by histomorphometric analysis. Serum was collected to measure calcitonin and sclerostin levels, inhibitors of bone resorption and formation, respectively. GLP-1R mRNA and protein expression were evaluated in the bone, bone marrow and bone cells using RT-PCR and immunohistochemistry. Primary osteoclasts and osteoblasts were cultured to evaluate the effect of GLP-1RA on bone resorption and formation in vitro. GLP-1RA significantly increased trabecular bone mass, connectivity and structure parameters but had no effect on cortical bone. There was no effect of GLP-1RA on bone formation in vivo but an increase in osteoclast number and osteoclast surfaces was observed with Ex-4. GLP-1R was expressed in bone marrow cells, primary osteoclasts and osteoblasts and in late osteocytic cell line. Both Ex-4 and LIR stimulated osteoclastic differentiation in vitro but slightly reduced the area resorbed per osteoclast. They had no effect on bone nodule formation in vitro. Serum calcitonin levels were increased and sclerostin levels decreased by Ex-4 but not by LIR. Thus, GLP-1RA can have beneficial effects on bone and the expression of GLP-1R in bone cells may imply that these effects are exerted directly on the tissue.
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK. Electronic address: mpereira@rvc.ac.uk.
authors: M
authors: M
authors: Pereira
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: J
authors: J
authors: Jeyabalan
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: C S
authors: CS
authors: Jørgensen
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: M
authors: M
authors: Hopkinson
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: A
authors: A
authors: Al-Jazzar
authors: INSERM UMR1033 and Université de Lyon, Lyon, France.
authors: J P
authors: JP
authors: Roux
authors: INSERM UMR1033 and Université de Lyon, Lyon, France.
authors: P
authors: P
authors: Chavassieux
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: I R
authors: IR
authors: Orriss
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: M E
authors: ME
authors: Cleasby
authors: Department of Comparative and Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
authors: C
authors: C
authors: Chenu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002116:Calcitonin / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D000077270:Exenatide; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D000069450:Liraglutide / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy*; D010052:Ovariectomy; D010455:Peptides / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D013977:Tibia / Q000000981:diagnostic imaging; D014688:Venoms / Q000008:administration & dosage*; D055114:X-Ray Microtomography; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002116:Calcitonin; D000077270:Exenatide; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D000069450:Liraglutide; D010455:Peptides; D012333:RNA, Messenger; D014688:Venoms; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C486030:Sost protein, mouse
keywords: Bone architecture; Diabetes; Glucagon-like peptide 1