Skeletal effects of a gastrin receptor antagonist in H+/K+ATPase beta subunit KO mice

• DOI: 10.1530/joe-16-0017
• Publication Date: 2016-06-21T02:58:44Z
• Authors: Kristin M Aasarød; Masoud Ramezanzad...; Maziar Shabestari; Mats P Mosti; Astrid K Stunes; Janne E Reseland; Vidar Beisvag; Erik Fink Eriksen; Arne K Sandvik; Reinhold G Erben; Christiane Schüler; Malcolm Boyce; Bjørn H Skallerud; Unni Syversen; Reidar Fossmark
• Keywords: Leptin; Mice, Knockout; Benzodiazepinones; Mice, Inbred BALB C; 0303 health sciences; Phenylurea Compounds; Osteocalcin; RANK Ligand; Drug Evaluation, Preclinical; Proton Pump Inhibitors; Bone and Bones; H(+)-K(+)-Exchanging ATPase; 03 medical and health sciences; Absorptiometry, Photon; Bone Density; Gastrins; Animals; Intercellular Signaling Peptides and Proteins; Osteoporosis; Female; Adaptor Proteins, Signal Transducing; Glycoproteins

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.