PT  - JOURNAL ARTICLE
AU  - Mermet, Morgane
AU  - Denom, Jessica
AU  - Mieczkowska, Aleksandra
AU  - Biggs, Emma
AU  - Gribble, Fiona M.
AU  - Reimann, Frank
AU  - Magnan, Christophe
AU  - Cruciani-Guglielmacci, Celine
AU  - Mabilleau, Guillaume
TI  - The GLP-1 analogue, exendin-4, improves bone material properties and strength through a central relay in ovariectomized mice
AID  - 10.1101/2024.10.05.616809
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.10.05.616809
4099  - http://biorxiv.org/content/early/2024/10/06/2024.10.05.616809.short
4100  - http://biorxiv.org/content/early/2024/10/06/2024.10.05.616809.full
AB  - Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized (OVX) BALB/c mice enhanced post-yield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the other hand, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy, but also suggest that GLP-1r agonists require a central relay yet to be identified to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.Competing Interest StatementThe authors have declared no competing interest.