Skeletal effects of the gastrin receptor antagonist netazepide in H+/K+ATPase beta-subunit deficient mice

Kristin Matre Aasarod; Masoud Ramezanzadeh Koldeh; Mats Peder Mosti; Astrid Kamilla Stunes; Bjorn Ivar Viggaklev; Janne Elin Reseland; Vidar Beisvag; Arne Kristian Sandvik; Bjorn Helge Skallerud; Unni Syversen; Reidar Fossmark

doi:10.1530/boneabs.3.OC3.6

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Bone Abstracts (2014) 3 OC3.6 | DOI: 10.1530/boneabs.3.OC3.6

ECTS2014 Oral Communications Osteoclasts, gastric hormones and HIF (6 abstracts)

Skeletal effects of the gastrin receptor antagonist netazepide in H+/K+ATPase beta-subunit deficient mice

Kristin Matre Aasarød ¹ , Masoud Ramezanzadeh Koldeh ² , Mats Peder Mosti ¹ , Astrid Kamilla Stunes ¹ , Bjørn Ivar Viggaklev ¹ , Janne Elin Reseland ³ , Vidar Beisvåg ¹ , Arne Kristian Sandvik ^1, , Bjørn Helge Skallerud ² , Unni Syversen ^1, & Reidar Fossmark ^1,

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¹Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway; ²Department of Structural Engeneering, NTNU, Trondheim, Norway; ³Department of Biomeaterials, Institute for Clinical Dentistry, UiO, Oslo, Norway; ⁴Department of Endocrinology, St. Olav’s Hospital, Trondheim, Norway; ⁵Department of Gastroenterology and Hepatology, St Olav’s Hospital, Trondheim, Norway.

Epidemiological studies suggest that patients using proton pump inhibitors (PPIs) have increased fracture risk. We have previously shown that H+/K+ATPase beta-subunit knockout (KO) mice have reduced BMD, BMC and mechanical bone strength compared to WT. Like users of PPIs, these mice have elevated serum gastrin levels due to high gastric pH. We wanted to study whether elevated gastrin influences bone quality in these mice.

Female KO and WT mice aged 6 weeks were randomly assigned to subcutaneous injection of either a gastrin receptor antagonist (netazepide 40 mg/kg per 2 weeks) or vehicle (polyethylene glycol) for 1 year. Whole body BMD and BMC were measured by DXA at initiation and before termination. Blood drawn at termination was analyzed for gastrin, RANKL, OPG, osteocalcin, leptin and sclerostin. Right femurs were examined with μCT and 3-point bending tests. The study was approved by the local Animal Welfare Committee.

KO mice had significantly (P<0.5) lower BMD (0.080 vs 0.070 g/cm²) and BMC (0.82 vs 0.61 g) at termination, while no significant differences between KO mice receiving netazepide and vehicle were observed. Cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD were significantly higher in WT compared to KO mice, and significantly higher in KO mice receiving netazepide than in the vehicle group. Stiffness was significantly higher in WT compared to KO, and tended to be higher in the KO group receiving netazepide (P=0.06). Breaking force tended to be higher in WT than KO mice (P=0.08), but no differences were seen between the netazepide and vehicle groups. Serological bone markers did not differ significantly between any of the groups.

The gastrin receptor antagonist netazeptide partly prevents bone loss and deterioration of bone quality in H^+/K⁺ATPase KO mice. Hypergastrinemia therefore, could play a part in the osteoporotic process in mice lacking the gastric proton pump.