GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells
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GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells. / Hansen, Morten S.; Soe, Kent; Christensen, Line L.; Fernandez-Guerra, Paula; Hansen, Nina W.; Wyatt, Rachael A.; Martin, Claire; Hardy, Rowan S.; Andersen, Thomas L.; Olesen, Jacob B.; Hartmann, Bolette; Rosenkilde, Mette M.; Kassem, Moustapha; Rauch, Alexander; Gorvin, Caroline M.; Frost, Morten.
I: European Journal of Endocrinology, Bind 188, Nr. 1, 004, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells
AU - Hansen, Morten S.
AU - Soe, Kent
AU - Christensen, Line L.
AU - Fernandez-Guerra, Paula
AU - Hansen, Nina W.
AU - Wyatt, Rachael A.
AU - Martin, Claire
AU - Hardy, Rowan S.
AU - Andersen, Thomas L.
AU - Olesen, Jacob B.
AU - Hartmann, Bolette
AU - Rosenkilde, Mette M.
AU - Kassem, Moustapha
AU - Rauch, Alexander
AU - Gorvin, Caroline M.
AU - Frost, Morten
PY - 2023
Y1 - 2023
N2 - 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, NF?B) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-?B (NF?B). 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.
AB - 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, NF?B) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-?B (NF?B). 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.
KW - GIPR
KW - bone remodeling
KW - osteoporosis
KW - resorption
KW - Akt1/2
KW - c-Src
KW - NFATc1
KW - NF kappa B
KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE
KW - KINASE-ACTIVITY
KW - RESORPTION
KW - DIFFERENTIATION
KW - MICE
KW - OBESITY
KW - LEADS
KW - TIME
U2 - 10.1093/ejendo/lvac004
DO - 10.1093/ejendo/lvac004
M3 - Journal article
C2 - 36747334
VL - 188
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
SN - 0804-4643
IS - 1
M1 - 004
ER -
ID: 351185850