GIP acts on multiple signaling pathways to uncouple bone resorption and formation

Clinical investigations show that short-term treatment with gastric inhibitory polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. We report that the GIP receptor (GIPR) is expressed in human osteoclasts. Furthermore, GIP inhibits osteoclastogenesis, delays and inhibits bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-?B (NF?B). Human osteoblasts also express GIPR. Although GIP improves osteoblast survival via cAMP and Akt-mediated pathways, expression of osteoblast-specific genes including RUNX2 and BGLAP and bone formation is not changed by GIP. Treatment of co-cultures of osteoclasts and osteoblasts with GIP decreased bone resorption but did not change formation. Antagonizing the GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoblasts and osteoclasts. Clinical studies are needed to determine if longer-term GIPR activation uncouples bone resorption and formation and improves bone mass Overall design: Osteoclasts differentiated in vitro from CD14 positive peripheral blood cells of 8 anonymous donors were stimulated with GIP (10nM) or not for 4 hours.