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.

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Chronic Lead Exposure Alters Mineral Properties in Alveolar Bone

Minerals ◽

10.3390/min11060642 ◽

2021 ◽

Vol 11 (6) ◽

pp. 642

Author(s):

Pedro Álvarez-Lloret ◽

Cristina Benavides-Reyes ◽

Ching-Ming Lee ◽

María Pilar Martínez ◽

María Inés Conti ◽

...

Keyword(s):

Bone Mineral ◽

Lead Exposure ◽

Alveolar Bone ◽

Bone Mineralization ◽

Bending Test ◽

Emission Spectrometry ◽

Mineral Density ◽

Trabecular Thickness ◽

Three Point Bending ◽

Chronic Lead Exposure

The objective of the present study was to investigate the effects of chronic lead exposure on the mineral properties of alveolar bone. For this purpose, female Wistar rats (n = 8) were exposed to 1000 ppm lead acetate in drinking water for 90 days, while the control group (n = 5) was treated with sodium acetate. The alveolar bone structure and chemical composition of the dissected mandibles were examined using micro-computed tomography (micro-CT), scanning electron microscopy (SEM), inductively coupled plasma optical emission spectrometry (ICP-OES), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), and X-ray diffraction (XRD) techniques to determine possible alterations in alveolar bone due to lead exposure. In addition, changes in bone mechanical properties were analysed using a three-point bending test. Exposure to lead induced notable changes in bone mineralization and properties, specifically a reduction of the trabecular thickness and bone mineral density. Furthermore, there was a reduction in carbonate content and an increase in bone mineral crystallinity. These changes in bone mineralization could be explained by an alteration in bone turnover due to lead exposure. Three-point bending showed a trend of decreased displacement at failure in the mandibles of lead-exposed rats, which could compromise the mechanical stability and normal development of the dentition.

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Programming Effect of the Parental Obesity on the Skeletal System of Offspring at Weaning Day

Animals ◽

10.3390/ani11020424 ◽

2021 ◽

Vol 11 (2) ◽

pp. 424

Author(s):

Radoslaw Piotr Radzki ◽

Marek Bienko ◽

Dariusz Wolski ◽

Monika Ostapiuk ◽

Pawel Polak ◽

...

Keyword(s):

Computed Tomography ◽

Bone Mineral ◽

High Energy ◽

Diet Group ◽

Male Rats ◽

Bending Test ◽

Male Rat ◽

Skeletal System ◽

Mineral Density ◽

Trabecular Thickness

Our study aimed to verify the hypothesis of the existence of a programming effect of parental obesity on the growth, development and mineralization of the skeletal system in female and male rat offspring on the day of weaning. The study began with the induction of obesity in female and male rats of the parental generation, using a high-energy diet (group F). Females and males of the control group received the standard diet (group S). After 90 days of dietary-induced obesity, the diet in group F was changed into the standard. Rats from groups F and S were mated to obtain offspring which stayed with their mothers until 21 days of age. Tibia was tested using dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), micro-computed tomography (µCT) and mechanical strength using the three-point bending test. Biochemical analysis of blood serum bone metabolism markers was performed. DXA analysis showed higher tibia bone mineral content (BMC) and area. pQCT measurements of cortical and trabecular tissue documented the increase of the volumetric bone mineral density and BMC of both bone compartments in offspring from the F group, while µCT of the trabecular tissue showed an increase in trabecular thickness and a decrease of its separation. Parental obesity, hence, exerts a programming influence on the development of the skeletal system of the offspring on the day of the weaning, which was reflected in the intensification of mineralization and increased bone strength.

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PHOSPHO1 is essential for normal bone fracture healing

Bone and Joint Research ◽

10.1302/2046-3758.76.bjr-2017-0140.r2 ◽

2018 ◽

Vol 7 (6) ◽

pp. 397-405 ◽

Cited By ~ 7

Author(s):

M. W. Morcos ◽

H. Al-Jallad ◽

J. Li ◽

C. Farquharson ◽

J. L. Millán ◽

...

Keyword(s):

Fracture Healing ◽

Bone Fracture ◽

Healing Process ◽

Bone Volume ◽

Fracture Repair ◽

Bending Test ◽

Bone Fracture Healing ◽

Trabecular Thickness ◽

Three Point Bending ◽

Normal Bone

Objectives Bone fracture healing is regulated by a series of complex physicochemical and biochemical processes. One of these processes is bone mineralization, which is vital for normal bone development. Phosphatase, orphan 1 (PHOSPHO1), a skeletal tissue-specific phosphatase, has been shown to be involved in the mineralization of the extracellular matrix and to maintain the structural integrity of bone. In this study, we examined how PHOSPHO1 deficiency might affect the healing and quality of fracture callus in mice. Methods Tibial fractures were created and then stabilized in control wild-type (WT) and Phospho1-/- mice (n = 16 for each group; mixed gender, each group carrying equal number of male and female mice) at eight weeks of age. Fractures were allowed to heal for four weeks and then the mice were euthanized and their tibias analyzed using radiographs, micro-CT (μCT), histology, histomorphometry and three-point bending tests. Results The μCT and radiographic analyses revealed a mild reduction of bone volume in Phospho1-/- callus, although it was not statistically significant. An increase in trabecular number and a decrease in trabecular thickness and separation were observed in Phospho1-/- callus in comparison with the WT callus. Histomorphometric analyses showed that there was a marked increase of osteoid volume over bone volume in the Phospho1-/- callus. The three-point bending test showed that Phospho1-/- fractured bone had more of an elastic characteristic than the WT bone. Conclusion Our work suggests that PHOSPHO1 plays an integral role during bone fracture repair and may be a therapeutic target to improve the fracture healing process. Cite this article: M. W. Morcos, H. Al-Jallad, J. Li, C. Farquharson, J. L. Millán, R. C. Hamdy, M. Murshed. PHOSPHO1 is essential for normal bone fracture healing: An Animal Study. Bone Joint Res 2018;7:397–405. DOI: 10.1302/2046-3758.76.BJR-2017-0140.R2.

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Relation between mechanical stiffness and vibration transmission of fracture callus: An experimental study on rabbit tibia

Proceedings of the Institution of Mechanical Engineers Part H Journal of Engineering in Medicine ◽

10.1243/0954411981534105 ◽

1998 ◽

Vol 212 (5) ◽

pp. 327-336 ◽

Cited By ~ 7

Author(s):

O Akkus ◽

F Korkusuz ◽

S Akin ◽

N Akkas

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Bending Test ◽

Bone Mineral Density Change ◽

Mineral Density ◽

Mechanical Stiffness ◽

Fracture Callus ◽

Vibration Transmission ◽

Three Point Bending ◽

Rabbit Tibia

It has been suggested that the vibration transmission across a fracture is affected by the stages of healing of the fracture callus. This study aims to correlate the change in vibration transmission with mechanical stiffness of the callus measured by three-point bending. The right tibiae of male, three-month old local albino rabbits were osteotomized and stabilized by intramedullary fixation following open reduction. The intramedullary rods were removed on the 15th, 28th, 42nd and 90th days postoperatively and the tibiae were excised for vibration, three-point bending and bone mineral density analysis by quantitative computerized tomography (QCT). Optimum time for clinical weight bearing was determined by checking the convergence of the vibration parameters of the fractured tibia to those of the unfractured contralateral. The conclusions obtained from curvature analysis, based on vibration experiments, were in considerable correlation (Spearman's rank correlation coefficient r = 0.93, p = 0.003) with the conclusions obtained from the three-point bending test data which reflected the mechanical condition of the bone by direct means. However, no correlation between bone mineral density change and vibration transmission was noted.

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Associations between Proton Pump Inhibitor and Histamine-2 Receptor Antagonist and Bone Mineral Density among Kidney Transplant Recipients

American Journal of Nephrology ◽

10.1159/000507470 ◽

2020 ◽

Vol 51 (6) ◽

pp. 433-441

Author(s):

Beini Lyu ◽

Karen E. Hansen ◽

Margaret R. Jorgenson ◽

Brad C. Astor

Keyword(s):

Bone Mineral Density ◽

Proton Pump Inhibitor ◽

Receptor Antagonist ◽

Kidney Transplant ◽

Bone Mineral ◽

Proton Pump ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Mineral Density ◽

T Score

Background: In the general population, use of proton pump inhibitor (PPI) has been linked to higher risk of osteoporotic fractures. PPI is commonly prescribed in kidney transplant recipients (KTRs). However, the effect of PPI on osteoporosis in KTRs is largely unstudied. Methods: A total of 1,774 adult KTRs in the Wisconsin Allograft Recipient Database with at least one eligible bone mineral density (BMD) measurement at least 3 months after transplantation were included in the analyses. Associations between use of PPI and histamine-2 receptor antagonist (H2RA) at 3 months after transplantation and subsequent slope of T-score were assessed. Results: A total of 1,478 (83.3%) participants were using a PPI at 3 months after transplantation. Compared to the use of H2RA, use of PPI was not significantly associated with annualized slope of hip T-score (β = –0.0039, 95% CI –0.00497 to 0.0021) or annualized slope of spine T-score (β = –0.017, 95% CI –0.049 to 0.083) after adjustment for potential confounders. Similarly, no significant association between use of PPI and slope of T-score was observed when defining PPI/H2RA exposure as use within 6 months of the initial BMD measurement, or only including participants with at least 2 BMD measurements, or stratified by different age and sex. Conclusions: Use of PPI was not associated with an increased rate of BMD loss in KTRs. Our results support previous findings that PPI use does not have a significant effect on bone mineral loss.

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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

International Journal of Molecular Sciences ◽

10.3390/ijms21030927 ◽

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.

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

Bone Abstracts ◽

10.1530/boneabs.3.oc3.6 ◽

2014 ◽

Cited By ~ 1

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

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Effects of short-term glucocorticoid administration on bone mineral density, biomechanics and microstructure in rats’ femur

Human & Experimental Toxicology ◽

10.1177/0960327116649674 ◽

2016 ◽

Vol 36 (3) ◽

pp. 287-294 ◽

Cited By ~ 1

Author(s):

Y Chen ◽

L Huang ◽

J Zhu ◽

K Wu

Keyword(s):

Bone Mineral Density ◽

Body Weight ◽

Bone Mineral ◽

Body Weight Gain ◽

Bending Test ◽

Whole Body ◽

Control Group ◽

Mineral Density ◽

Short Term ◽

Trabecular Thickness

The effects of short-term use of oral glucocorticoid (GC) on the skeleton are not well defined. To address this gap, the influences of 7 days, 21 days of GC administration on femurs of intact rats were investigated. Forty 4-month-old female Sprague–Dawley rats were randomly divided into control group (Cont) and prednisone-treated group (Pre) and administered either distilled water or prednisone acetate at doses of 3.5 mg/kg/day for 0, 7 and 21 days, respectively. All the femurs were harvested for dual-energy X-ray absorptiometry scan, biomechanical testing and micro computed tomography scan. The whole body weight, femur bone mineral density (BMD), all three-point bending test parameters, microstructural parameters increased or improved significantly in Cont at day 21 when compared to day 0. The whole body weight, distal femur BMD, Young’s modulus, bending stiffness, density of tissue volume and trabecular thickness (Tb.Th) decreased, while structure model index and trabecular separation (Tb.Sp) increased significantly in Pre at day 21 when compared to age-matched control but had no significant differences between day 7 and day 21. Our data demonstrate that 7-day use of prednisone does not influence on rats’ femur, and 21-day use of prednisone slows in rate of whole body weight gain, decreases femur metaphysis BMD and bone stiffness which mainly due to the deteriorated bone microstructure.

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