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

2014 ◽  
Author(s):  
Kristin Matre Aasarod ◽  
Masoud Ramezanzadeh Koldeh ◽  
Mats Peder Mosti ◽  
Astrid Kamilla Stunes ◽  
Bjorn Ivar Viggaklev ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Beta Subunit ◽  
Gastrin Receptor ◽  
Skeletal Effects ◽  
Deficient Mice

scholarly journals Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

2020 ◽  
Vol 21 (3) ◽  
pp. 927
Author(s):  
Kristin Matre Aasarød ◽  
Helge Lyder Waldum ◽  
Astrid Kamilla Stunes ◽  
Arne Kristian Sandvik ◽  
Arnar Flatberg ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Receptor Antagonist ◽  
Cyst Formation ◽  
Beta Subunit ◽  
Cell Hyperplasia ◽  
Gastrin Receptor ◽  
Increased Risk ◽  
Gastric Corpus ◽  
Spasmolytic Polypeptide

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

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

2016 ◽  
Vol 230 (2) ◽  
pp. 251-262 ◽  
Author(s):  
Kristin M Aasarød ◽  
Masoud Ramezanzadehkoldeh ◽  
Maziar Shabestari ◽  
Mats P Mosti ◽  
Astrid K Stunes ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Bone Quality ◽  
Bone Mineral ◽  
Proton Pump ◽  
Beta Subunit ◽  
Bending Test ◽  
Trabecular Thickness ◽  
Gastrin Receptor ◽  
Three Point Bending ◽  
Cck2 Receptor

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.

scholarly journals Role of interleukin-25 in development of spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice

2017 ◽  
Vol 12 ◽  
pp. 62-65
Author(s):  
Yasuharu Abe ◽  
Aya Nambu ◽  
Sachiko Yamaguchi ◽  
Ayako Takamori ◽  
Hajime Suto ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist ◽  
Interleukin 25 ◽  
Deficient Mice

scholarly journals Rimonabant, a Selective Cannabinoid CB1 Receptor Antagonist, Inhibits Atherosclerosis in LDL Receptor–Deficient Mice

2009 ◽  
Vol 29 (1) ◽  
pp. 12-18 ◽  
Author(s):  
Frédérique Dol-Gleizes ◽  
Réjane Paumelle ◽  
Virgile Visentin ◽  
Anne-Marie Marés ◽  
Perrine Desitter ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ldl Receptor ◽  
Cb1 Receptor ◽  
Cannabinoid Cb1 Receptor ◽  
Cb1 Receptor Antagonist ◽  
Deficient Mice ◽  
Cannabinoid Cb1 Receptor Antagonist

scholarly journals Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist–Deficient Mice

2000 ◽  
Vol 191 (2) ◽  
pp. 313-320 ◽  
Author(s):  
Reiko Horai ◽  
Shinobu Saijo ◽  
Hidetoshi Tanioka ◽  
Susumu Nakae ◽  
Katsuko Sudo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Type Ii Collagen ◽  
Cytokine Network ◽  
Gene Deficiency ◽  
Double Stranded Dna ◽  
Inflammatory Arthropathy ◽  
Factor Α ◽  
Deficient Mice

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra–deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.

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