Skeletal effects of a gastrin receptor antagonist in H+/K+ATPase beta subunit KO mice.
Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H(+)/K(+)ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young's modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway kristin.aasarod@ntnu.no.
Kristin M
KM
Aasarød
Department of Structural EngineeringNTNU, Trondheim, Norway.
Masoud
M
Ramezanzadehkoldeh
Department of BiomaterialsInstitute of Clinical Dentistry, University of Oslo, Oslo, Norway.
Maziar
M
Shabestari
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway.
Mats P
MP
Mosti
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway.
Astrid K
AK
Stunes
Department of BiomaterialsInstitute of Clinical Dentistry, University of Oslo, Oslo, Norway.
Janne E
JE
Reseland
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway.
Vidar
V
Beisvag
Institute of Clinical MedicineUniversity of Oslo, Oslo, Norway.
Erik Fink
EF
Eriksen
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway Department of Gastroenterology and HepatologySt. Olav's Hospital, Trondheim, Norway Centre of Molecular Inflammation ResearchNTNU, Trondheim, Norway.
Arne K
AK
Sandvik
Department of Biomedical SciencesUniversity of Veterinary Medicine Vienna, Vienna, Austria.
Reinhold G
RG
Erben
Department of Biomedical SciencesUniversity of Veterinary Medicine Vienna, Vienna, Austria.
Christiane
C
Schüler
Hammersmith Medicines ResearchLondon, UK.
Malcolm
M
Boyce
Department of Structural EngineeringNTNU, Trondheim, Norway.
Bjørn H
BH
Skallerud
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway Department of EndocrinologySt. Olav's Hospital, Trondheim, Norway.
Unni
U
Syversen
Department of Cancer Research and Molecular MedicineNTNU, Trondheim, Norway Department of Gastroenterology and HepatologySt. Olav's Hospital, Trondheim, Norway.
Reidar
R
Fossmark
D015502:Absorptiometry, Photon; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005755:Gastrins / Q000097:blood; D006023:Glycoproteins / Q000097:blood; D017506:H(+)-K(+)-Exchanging ATPase / Q000172:deficiency* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000139:chemically induced / Q000517:prevention & control*; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000009:adverse effects; D053245:RANK Ligand / Q000097:blood; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000187:drug effects; D055114:X-Ray Microtomography
D048868:Adaptor Proteins, Signal Transducing; D001570:Benzodiazepinones; D005755:Gastrins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D053245:RANK Ligand; D043887:Receptor, Cholecystokinin B; C486030:Sost protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D017506:H(+)-K(+)-Exchanging ATPase; C104428:YF 476
acid inhibition; bone; gastrin; netazepide; osteoporosis