title: Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption.
abstract: A role for glucose-dependent insulinotropic polypeptide (GIP) in controlling bone resorption has been suspected. However uncertainty remains to identify whether GIP act directly on osteoclasts. The aim of the present study were (i) to identify in different osteoclast differentiation models (human peripheral blood mononuclear cells-PBMC, murine bone marrow macrophage-BMM and murine Raw 264.7 cells) whether GIP was capable of reducing osteoclast formation and resorption; (ii) ascertain whether the highly potent GIP analogue N-AcGIP was capable of inducing a response at lower concentrations and (iii) to decipher the molecular mechanisms responsible for such effects. [d-Ala(2)]-GIP dose-dependently reduced osteoclast formation at concentration as low as 1nM in human PBMC and 10nM in murine BMM cultures. Furthermore, [d-Ala(2)]-GIP also reduced the extent of osteoclast resorption at concentration as low as 1nM in human PBMC and murine BMM cultures. The mechanism of action of [d-Ala(2)]-GIP appeared to be mediated by reduction in intracellular calcium concentration and oscillation that subsequently inhibited calcineurin activity and NFATc1 nuclear translocation. The potency of the highly potent N-AcGIP was determined and highlighted an effect on osteoclast formation and resorption at concentration ten times lower than observed with [d-Ala(2)]-GIP in vitro. Furthermore, N-AcGIP was also capable of reducing the number of osteoclast in ovariectomized mice as well as the circulating level of type I collagen C-telopeptide. Pharmacological concentrations required for reducing osteoclast formation and resorption provide the impetus to design and exploit enzymatically stable GIP analogues for the treatment of bone resorption disorders in humans.
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France. Electronic address: guillaume.mabilleau@univ-angers.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mabilleau
authors.affiliation: SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Perrot
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mieczkowska
authors.affiliation: Lentivec, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Boni
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Diabetes Research Group, Biomedical Sciences Research Institute, University of Ulster, BT52 1SA Coleraine, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Diabetes Research Group, Biomedical Sciences Research Institute, University of Ulster, BT52 1SA Coleraine, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, University of Angers, 49933 ANGERS Cedex, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chappard
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010447:Peptide Hydrolases; D000262:Adenylyl Cyclases; D002118:Calcium
keywords: Bone resorption; N-AcGIP; Osteoclast; Osteoclastogenesis; [d-Ala(2)]-GIP