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Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength

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Abstract

Summary

A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone - and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology.

Introduction

The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice.

Methods

Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively.

Results

As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy.

Conclusions

This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

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Acknowledgments

The authors are grateful to N Gaborit and G Brossard for their help with microCT. This work was supported by grants from the Bioregos2 Program and the University of Ulster Proof of Principle Funding Program.

Conflicts of interest

Aleksandra Mieczkowska, Sity Mansur, Beatrice Bouvard, Peter R Flatt, Bernard Thorens, Nigel Irwin, Daniel Chappard, and Guillaume Mabilleau have no conflict of interest to declare.

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Authors and Affiliations

  1. GEROM-LHEA UPRES EA 4658, Institut de Biologie en Santé, LUNAM Université, 4 rue larrey, 49933, Angers Cedex 09, France

    A. Mieczkowska, B. Bouvard, D. Chappard & G. Mabilleau

  2. SCIAM, Institut de Biologie en Santé, LUNAM Université, Angers, France

    D. Chappard & G. Mabilleau

  3. School of Biomedical Sciences, Ulster University, Coleraine, UK

    S. Mansur, P. R. Flatt & N. Irwin

  4. Service de Rhumatologie, CHU d’Angers, Angers, France

    B. Bouvard

  5. Centre for integrative genomics, University of Lausanne, Lausanne, Switzerland

    B. Thorens

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  1. A. Mieczkowska
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  8. G. Mabilleau
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Correspondence to G. Mabilleau.

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Mieczkowska, A., Mansur, S., Bouvard, B. et al. Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength. Osteoporos Int 26, 209–218 (2015). https://doi.org/10.1007/s00198-014-2845-8

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  • DOI: https://doi.org/10.1007/s00198-014-2845-8

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