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

Autor:	Hansen MS; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark.; Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom.; Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom., Søe K; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark.; Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Molecular Medicine, University of Southern Denmark, Odense C DK-5000, Denmark., Christensen LL; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark., Fernandez-Guerra P; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark., Hansen NW; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark., Wyatt RA; Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom.; Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom., Martin C; Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom., Hardy RS; Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom., Andersen TL; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark.; Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Molecular Medicine, University of Southern Denmark, Odense C DK-5000, Denmark., Olesen JB; Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark., Hartmann B; Department of Biomedical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Rosenkilde MM; Department of Biomedical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Kassem M; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark., Rauch A; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark.; Steno Diabetes Centre Odense, Odense University Hospital, Odense C DK-5000, Denmark., Gorvin CM; Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom.; Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom., Frost M; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark.; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark.; Steno Diabetes Centre Odense, Odense University Hospital, Odense C DK-5000, Denmark.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2023 Jan 10; Vol. 188 (1).
DOI:	10.1093/ejendo/lvac004
Abstrakt:	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. Competing Interests: Conflicts of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)
Databáze:	MEDLINE
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