Development of a first-in-class unimolecular dual GIP/GLP-2 analogue, GL-0001, for the treatment of bone fragility

Benoit Gobron, Malory Couchot, Nigel Irwin, Erick Legrand, Béatrice Bouvard, Guillaume Mabilleau

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
76 Downloads (Pure)

Abstract

Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Original languageEnglish
Pages (from-to)733-748
Number of pages16
JournalJournal of Bone and Mineral Research
Volume38
Issue number5
Early online date27 Feb 2023
DOIs
Publication statusPublished online - 27 Feb 2023

Bibliographical note

Funding Information:
The authors are grateful to Dr. Boni (Lentivec platform, University of Angers) for his help in the cloning and preparation of plasmid encoding human GIPr and GLP‐2r, the staff of the SCAHU platform (University of Angers) for animal care and to Ms. Mieczkowska (HiMolA Platform, University of Angers) for her help in Fourier transform microspectroscopy. We are thankful to Prof. Peter Gardner (University of Manchester) for supplying the Mie scattering correction routine for MATLAB and Prof. Rob van't Hof (University of Liverpool) for supplying the CalceinHisto software. Part of this work was supported by a grant from the SATT Ouest valorization (Grant DV2541).

Publisher Copyright:
© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Funding Information:
The authors are grateful to Dr. Boni (Lentivec platform, University of Angers) for his help in the cloning and preparation of plasmid encoding human GIPr and GLP-2r, the staff of the SCAHU platform (University of Angers) for animal care and to Ms. Mieczkowska (HiMolA Platform, University of Angers) for her help in Fourier transform microspectroscopy. We are thankful to Prof. Peter Gardner (University of Manchester) for supplying the Mie scattering correction routine for MATLAB and Prof. Rob van't Hof (University of Liverpool) for supplying the CalceinHisto software. Part of this work was supported by a grant from the SATT Ouest valorization (Grant DV2541).

Funding Information:
The authors are grateful to Dr. Boni (Lentivec platform, University of Angers) for his help in the cloning and preparation of plasmid encoding human GIPr and GLP‐2r, the staff of the SCAHU platform (University of Angers) for animal care and to Ms. Mieczkowska (HiMolA Platform, University of Angers) for her help in Fourier transform microspectroscopy. We are thankful to Prof. Peter Gardner (University of Manchester) for supplying the Mie scattering correction routine for MATLAB and Prof. Rob van't Hof (University of Liverpool) for supplying the CalceinHisto software. Part of this work was supported by a grant from the SATT Ouest valorization (Grant DV2541).

Publisher Copyright:
© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords

  • unimolecular dual GIP/GLP-2 analogue
  • bone material properties
  • bone fragility
  • UNIMOLECULAR DUAL GIP/GLP‐2 ANALOGUE
  • BONE MATERIAL PROPERTIES
  • BONE FRAGILITY
  • Research Articles
  • Research Article
  • UNIMOLECULAR DUAL GIP/GLP-2 ANALOGUE

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