title: Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties.
abstract: Bone remodeling is under complex regulation from nervous, hormonal and local signals, including gut hormones. Among the gut hormones, a role for the glucose-dependent insulinotropic polypeptide (GIP) has been suggested. However, the rapid degradation of GIP in the bloodstream by the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) precludes therapeutic use. To circumvent this problem, a series of N-terminally modified GIP agonists have been developed, with N-AcGIP being the most promising. The aims of the present study were to investigate the effects of N-AcGIP on bone at the micro-level using trabecular and cortical microstructural morphology, and at the tissue-level in rats. Copenhagen rats were randomly assigned into control or N-AcGIP-treated groups and received daily injection for 4 weeks. Bone microstructural morphology was assessed by microCT and dynamic histomorphometry and tissue-level properties by nanoindentation, qBEI and infra-red microscopy. Four week treatment with N-AcGIP did not alter trabecular or cortical microstructural morphology. In addition, no significant modifications of mechanical response and properties at the tissue-level were observed in trabecular bone. However, significant augmentations in maximum load (12%), hardness (14%), indentation modulus (13%) and dissipated energy (16%) were demonstrated in cortical bone. These beneficial modifications of mechanical properties at the tissue-level were associated with increased mineralization (22%) and collagen maturity (13%) of the bone matrix. Taken together, the results support a beneficial role of GIP, and particularly stable analogs such as N-AcGIP, on tissue material properties of bone.
authors.affiliation: LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; LUNAM Université, SCIAM, Institut de Biologie en Santé, Angers, France. Electronic address: guillaume.mabilleau@univ-angers.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mabilleau
authors.affiliation: LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mieczkowska
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, U K.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; Service de Rhumatologie, CHU d'Angers, Angers, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Simon
authors.affiliation: LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; Service de Rhumatologie, CHU d'Angers, Angers, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Audran
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, U K.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; LUNAM Université, SCIAM, Institut de Biologie en Santé, Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chappard
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D051381:Rats
chemical_list: D005749:Gastric Inhibitory Polypeptide; D003094:Collagen
keywords: Bone material properties; Collagen maturity; N-AcGIP; Nanoindentation; qBEI