GIP receptor reduces osteoclast activity and improves osteoblast survival by activating multiple signaling pathways

Bone is a dynamic tissue that is remodeled throughout life by bone resorbing osteoclasts and bone forming osteoblasts, to adapt to physiological or mechanical demands. These processes are impaired in osteoporosis, and understanding how bone remodeling is regulated could improve anti-osteoporotic treatments. Clinical investigations show that short-term treatment with glucose-dependent insulinotropic polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. However, evidence for direct effects of GIP intracellular signaling and functions in mature human osteoclasts and osteoblasts have not been investigated. We report that the GIP receptor (GIPR) is robustly expressed in mature human osteoclasts. Exposure of osteoclasts to GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (cAMP, Src, Akt, calcium, p38) to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-κB (NFκB). Human osteoblasts also express GIPR, and GIP improves osteoblast survival via cAMP and Akt-mediated pathways. GIP treatment of co-cultures of osteoclasts and osteoblasts also decreased bone resorption. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. This study demonstrates that GIP inhibits bone resorption and improves survival of human osteoblasts, which could increase bone mass and strength, supporting clinical investigations of the effect of GIP on bone. Moreover, this study demonstrates that GIPR agonism could be beneficial in the treatment of disorders of bone remodeling, such as osteoporosis. One-sentence Summary GIP acts directly on bone cells to regulate bone remodeling

[1]  J. Holst,et al.  GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. , 2022, Pharmacological research.

[2]  F. Rivadeneira,et al.  Bone fragility in diabetes: novel concepts and clinical implications. , 2022, The lancet. Diabetes & endocrinology.

[3]  N. Grarup,et al.  Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes , 2021, Frontiers in Cell and Developmental Biology.

[4]  M. Frost,et al.  Alliances of the gut and bone axis. , 2021, Seminars in cell & developmental biology.

[5]  J. Rosenstock,et al.  Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. , 2021, The New England journal of medicine.

[6]  J. Holst,et al.  The Antiresorptive Effect of GIP, But Not GLP‐2, Is Preserved in Patients With Hypoparathyroidism—A Randomized Crossover Study , 2021, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[7]  Yuan Cheng,et al.  Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism , 2020, Nature Communications.

[8]  J. Holst,et al.  The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. , 2020, Bone.

[9]  M. Rosenkilde,et al.  Molecular interactions of full-length and truncated GIP peptides with the GIP receptor – A comprehensive review , 2019, Peptides.

[10]  J. Holst,et al.  GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men. , 2019, Bone.

[11]  J. Holst,et al.  Separate and Combined Effects of GIP and GLP-1 Infusions on Bone Metabolism in Overweight Men Without Diabetes. , 2019, The Journal of clinical endocrinology and metabolism.

[12]  J. Delaissé,et al.  Catabolic activity of osteoblast lineage cells contributes to osteoclastic bone resorption in vitro , 2019, Journal of Cell Science.

[13]  J. Bassett,et al.  The bone remodelling cycle , 2018, Annals of clinical biochemistry.

[14]  P. Rorsman,et al.  AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity , 2018, Cell reports.

[15]  J. Daugaard,et al.  A novel GIP analogue, ZP4165, enhances glucagon‐like peptide‐1‐induced body weight loss and improves glycaemic control in rodents , 2018, Diabetes, obesity & metabolism.

[16]  J. Delaissé,et al.  Coupling of Bone Resorption and Formation in Real Time: New Knowledge Gained From Human Haversian BMUs , 2017, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  J. Delaissé,et al.  Time-lapse reveals that osteoclasts can move across the bone surface while resorbing , 2017, Journal of Cell Science.

[18]  D. Chappard,et al.  Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption. , 2016, Bone.

[19]  S. Avnet,et al.  Energy metabolism in osteoclast formation and activity. , 2016, The international journal of biochemistry & cell biology.

[20]  J. Delaissé,et al.  Early reversal cells in adult human bone remodeling: osteoblastic nature, catabolic functions and interactions with osteoclasts , 2016, Histochemistry and Cell Biology.

[21]  J. Holst,et al.  N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor , 2016, British journal of pharmacology.

[22]  M. Ding,et al.  Pit- and trench-forming osteoclasts: a distinction that matters , 2015, Bone Research.

[23]  Soo Young Lee,et al.  The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors , 2015, Science Signaling.

[24]  R. Seeley,et al.  A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents , 2014, Nature Medicine.

[25]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[26]  M. Christensen,et al.  Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. , 2014, The Journal of clinical endocrinology and metabolism.

[27]  J. Delaissé,et al.  Osteoclast Fusion is Based on Heterogeneity Between Fusion Partners , 2014, Calcified Tissue International.

[28]  Piotr J. Balwierz,et al.  ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs , 2014, Genome research.

[29]  P. Rotwein,et al.  Selective Signaling by Akt1 Controls Osteoblast Differentiation and Osteoblast-Mediated Osteoclast Development , 2011, Molecular and Cellular Biology.

[30]  R. Russell,et al.  Bisphosphonates: the first 40 years. , 2011, Bone.

[31]  Hong-Hee Kim,et al.  Adenylate cyclase and calmodulin‐dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA‐NFATc1 pathway , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  J. Delaissé,et al.  Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[34]  Matthew D. Young,et al.  Gene ontology analysis for RNA-seq: accounting for selection bias , 2010, Genome Biology.

[35]  Akira Yamaguchi,et al.  Regulation of osteoclast differentiation and function by the CaMK-CREB pathway , 2006, Nature Medicine.

[36]  Yuichiro Yamada,et al.  Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. , 2006, Molecular endocrinology.

[37]  Y. Nogi,et al.  Essential Role of p38 Mitogen-activated Protein Kinase in Cathepsin K Gene Expression during Osteoclastogenesis through Association of NFATc1 and PU.1* , 2004, Journal of Biological Chemistry.

[38]  L. Luttrell,et al.  Not so strange bedfellows: G-protein-coupled receptors and Src family kinases , 2004, Oncogene.

[39]  Archana Sanjay,et al.  Src Kinase Activity Is Essential for Osteoclast Function* , 2004, Journal of Biological Chemistry.

[40]  K. Taskén,et al.  Protein Kinase A Intersects Src Signaling in Membrane Microdomains* , 2003, The Journal of Biological Chemistry.

[41]  H. Koh,et al.  Cyclic AMP Inhibits Akt Activity by Blocking the Membrane Localization of PDK1* , 2001, The Journal of Biological Chemistry.

[42]  H. Rasmussen,et al.  Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. , 2000, Endocrinology.

[43]  T. Soderling,et al.  Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway , 1998, Nature.

[44]  Keli Xu,et al.  Calcium oscillations increase the efficiency and specificity of gene expression , 1998, Nature.

[45]  C. Cooper,et al.  Epidemiology of osteoporosis. , 2002, Best practice & research. Clinical rheumatology.

[46]  R. Pederson,et al.  Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. , 1995, Endocrinology.

[47]  Sakae Tanaka,et al.  Wortmannin, a specific inhibitor of phosphatidylinositol‐3 kinase, blocks osteoclastic bone resorption , 1995, FEBS letters.

[48]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[49]  J. Holst,et al.  GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2. , 2019, Bone.

[50]  J. Holst,et al.  Glucose-Dependent Insulinotropic Polypeptide (GIP) Inhibits Bone Resorption Independently of Insulin and Glycemia , 2018, The Journal of clinical endocrinology and metabolism.

[51]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[52]  P. De Camilli,et al.  The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts. , 2008, Molecular biology of the cell.

[53]  Chantal Wouters,et al.  An exploratory study , 2003 .

[54]  J. Caamaño,et al.  Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. , 1997, Nature medicine.

[55]  U. Lerner,et al.  Comparison between the effects of forskolin and calcitonin on bone resorption and osteoclast morphology in vitro. , 1989, Bone.