GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells

Morten S Hansen, Kent Søe, Line Lindorf Christensen, Paula Fernandez Guerra, Nina Wærling Hansen, Rachel A. Wyatt, Claire S. Martin, Rowan S. Hardy, Thomas Levin Andersen, Jacob Bastholm Olesen, Bolette Hartmann, Mette Marie Rosenkilde, Moustapha Kassem, Alexander Rauch, Caroline M Gorvin*, Morten Frost*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

OBJECTIVE: Drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) are emerging as treatments for type-2 diabetes and obesity. GIP acutely decreases serum markers of bone resorption and transiently increases bone formation markers in short-term clinical investigations. However, it is unknown whether GIP acts directly on bone cells to mediate these effects. Using a GIPR-specific antagonist, we aimed to assess whether GIP acts directly on primary human osteoclasts and osteoblasts.

METHODS: Osteoclasts were differentiated from human CD14+ monocytes and osteoblasts from human bone. GIPR expression was determined using RNA-seq in primary human osteoclasts and in situ hybridization in human femoral bone. Osteoclastic resorptive activity was assessed using microscopy. GIPR signaling pathways in osteoclasts and osteoblasts were assessed using LANCE cAMP and AlphaLISA phosphorylation assays, intracellular calcium imaging and confocal microscopy. The bioenergetic profile of osteoclasts was evaluated using Seahorse XF-96.

RESULTS: GIPR is robustly expressed in mature human osteoclasts. GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (Src, cAMP, Akt, p38, Akt, NFκB) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-κB (NFκB). Osteoblasts also expressed GIPR, and GIP improved osteoblast survival. Decreased bone resorption and improved osteoblast survival were also observed after GIP treatment of osteoclast-osteoblast co-cultures. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts.

CONCLUSIONS: GIP inhibits bone resorption and improves survival of human osteoblasts, indicating that drugs targeting GIPR may impair bone resorption, whilst preserving bone formation.

Original languageEnglish
Article numberlvac004
JournalEuropean Journal of Endocrinology
Volume188
Issue number1
Number of pages14
ISSN0804-4643
DOIs
Publication statusPublished - 2023

Keywords

  • Bone Resorption/drug therapy
  • Bone and Bones/metabolism
  • Cell Differentiation
  • Humans
  • Osteoblasts/metabolism
  • Osteoclasts/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism

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