GLP-2 administration in ovariectomized mice enhances collagen maturity but did not improve bone strength

Gobron, Benoît; Bouvard, Béatrice; Legrand, Érick; Chappard, Daniel; Mabilleau, Guillaume

doi:10.1016/j.bonr.2020.100251

Cited by 6 publications

(22 citation statements)

References 51 publications

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“…This process was dependent on adenylyl cyclase as the use of a specific adenylyl cyclase inhibitor, 2’,5’dideoxyadenosine, blocked this effect. This is interesting and in agreement with already published literature where higher collagen maturity was observed in GLP-2-treated ovariectomized animals ( 16 ). Previously, effects of GLP-2 action on bone resorption have been hypothesized through a parathyroid hormone-dependent mechanism ( 31 , 32 ).…”

Section: Discussionsupporting

confidence: 93%

“…Several lines of evidence suggest that peptides produced by enteroendocrine cells are beneficial for bone quality and strength (16,(24)(25)(26)(27)(28). Indeed, GLP-2 was previously shown to reduce circulating markers of bone resorption rapidly after administration and to enhance bone mineral density in postmenopausal women (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…Depending on tissue-specific splicing, proglucagon mRNA gives rise to several peptide including glucagon (GCG), glicentin-related peptide, oxyntomodulin, glucacon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) (15). Administration of exogenous oxyntomodulin, GLP-1, or GLP-2 has previously evidenced beneficial effects on bone quality and especially collagen maturity in vivo (16)(17)(18). However, despite the fact that GLP-1 and GLP-2 receptors have previously been evidenced in murine and human osteoblasts (19,20), little is known whether the observed effects are due to direct activation of osteoblast cells.…”

Section: Introductionmentioning

confidence: 99%

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[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

et al. 2021

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Bone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

et al. 2021

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“…• Collagen maturity determined as the area ratio of subbands peaking at ~1660 cm -1 (mature crosslinks) and ~1690 cm -1 (Immature crosslinks). The respective contribution of mature and immature crosslinks to total collagen crosslinks was computed to evaluate post-processing of collagen molecules as previously reported [17];…”

Section: Fourier-transform Infrared Microspectroscopy and Imagingmentioning

confidence: 99%

Dapagliflozin and Liraglutide Therapies Rapidly Enhanced Bone Material Properties and Matrix Biomechanics at Bone Formation Site in a Type 2 Diabetic Mouse Model

et al. 2020

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Aim: To compare head-to-head the effects of dapagliflozin and liraglutide on bone strength and bone material properties in a pre-clinical model of diabetes-obesity. Materials and methods: Combined low-dose streptozotocin and high fat feeding were employed in mice to promote obesity, insulin resistance and hyperglycaemia. Mice were administered daily for 28 days with saline vehicle, 1mg/kg dapagliflozin or 25 nmol/kg liraglutide. Bone strength was assessed by three-point bending and nanoindentation. Bone material properties were investigated by Fourier transform infrared microspectroscopy/imaging. Results: Although diabetic controls presented with dramatic reductions in mechanical strength, no deterioration of bone microarchitecture was apparent. At the tissue level, significant alterations in phosphate/amide ratio, carbonate/phosphate ratio, tissue water content, crystal size index, collagen maturity and collagen glycation were observed and linked to alteration of matrix biomechanics. Dapagliflozin and liraglutide failed to improve bone strength by 3-point bending or bone microarchitecture during the 28-day-treatment period. At bone formation site, dapagliflozin enhanced phosphate/amide ratio, mineral maturity, and reduced tissue water content, crystal size index and collagen glycation. Liraglutide had significant effects on phosphate/amide ratio, tissue water content, crystal size index, mature collagen crosslinks, collagen maturity and collagen glycation. At bone formation site, both drugs modulated matrix biomechanics. Conclusions: This study highlighted that these two molecules are effective in improving bone material properties and modulating matrix biomechanics at bone formation site. This study also highlighted that the resulting effects on bone material properties are not identical between dapagliflozin and liraglutide and not only mediated by lower blood glucose.

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“…Indeed, these peptides maintain optimal bone ECM material properties, through a cAMP-dependent pathway (13-16) . This concept was also reinforced by the use of first generation GIPr- and GLP-2r-specific analogues in several mice models of bone fragility (17-21) . Furthermore, head-to-head comparison in preclinical model of bone fragility suggested that single GIP or GLP-2 analogues improved resistance to fracture to the same magnitude level than observed with bisphosphonates (17,22) .…”

Section: Introductionmentioning

confidence: 99%

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

Gobron

Couchot

Irwin

et al. 2022

Preprint

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Due to ageing 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 ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. 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 of bone fragility.

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GLP-2 administration in ovariectomized mice enhances collagen maturity but did not improve bone strength

Cited by 6 publications

References 51 publications

[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

Dapagliflozin and Liraglutide Therapies Rapidly Enhanced Bone Material Properties and Matrix Biomechanics at Bone Formation Site in a Type 2 Diabetic Mouse Model

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

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