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, Serra Ucer Ozgurel Department of Nutritional Sciences, University of Texas , Austin, TX 78723, United States Search for other works by this author on: Oxford Academic Perla C Reyes Fernandez Department of Physical Therapy, Indiana University –Purdue University , Indianapolis, IN 46202, United States Search for other works by this author on: Oxford Academic Krittikan Chanpaisaeng National Center for Genetic Engineering and Biotechnology , Pathum Thani 12120, Thailand Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University , Bangkok 10330, Thailand Search for other works by this author on: Oxford Academic James C Fleet Department of Nutritional Sciences, University of Texas , Austin, TX 78723, United States Corresponding author: James C. Fleet, Department of Nutritional Science, Dell Pediatric Research Institute, University of Texas, 1400 Barbara Jordan Blvd, University of Texas, Austin, TX 78723, United States (james.fleet@austin.utexas.edu) Search for other works by this author on: Oxford Academic
Journal of Bone and Mineral Research, Volume 39, Issue 3, March 2024, Pages 315–325, https://doi.org/10.1093/jbmr/zjae011
Published:
31 January 2024
Article history
Received:
14 July 2023
Revision received:
20 December 2023
Accepted:
10 January 2024
Published:
31 January 2024
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Serra Ucer Ozgurel, Perla C Reyes Fernandez, Krittikan Chanpaisaeng, James C Fleet, Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system, Journal of Bone and Mineral Research, Volume 39, Issue 3, March 2024, Pages 315–325, https://doi.org/10.1093/jbmr/zjae011
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Abstract
Environmental factors and genetic variation individually impact bone. However, it is not clear how these factors interact to influence peak bone mass accrual. Here we tested whether genetically programmed high bone formation driven by missense mutations in the Lrp5 gene (Lrp5A214V) altered the sensitivity of mice to an environment of inadequate dietary calcium (Ca) intake. Weanling male Lrp5A214V mice and wildtype littermates (control) were fed AIN-93G diets with 0.125%, 0.25%, 0.5% (reference, basal), or 1% Ca from weaning until 12 weeks of age (ie, during bone growth). Urinary Ca, serum Ca, Ca regulatory hormones (PTH, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)), bone parameters (μCT, ash), and renal/intestinal gene expression were analyzed. As expected, low dietary Ca intake negatively impacted bones and Lrp5A214V mice had higher bone mass and ash content. Although bones of Lrp5A214V mice have more matrix to mineralize, their bones were not more susceptible to low dietary Ca intake. In control mice, low dietary Ca intake exerted expected effects on serum Ca (decreased), PTH (increased), and 1,25(OH)2D3 (increased) as well as their downstream actions (ie, reducing urinary Ca, increasing markers of intestinal Ca absorption). In contrast, Lrp5A214V mice had elevated serum Ca with a normal PTH response but a blunted 1,25(OH)2D3 response to low dietary Ca that was reflected in the renal 1,25(OH)2D3 producing/degrading enzymes, Cyp27b1 and Cyp24a1. Despite elevated serum Ca in Lrp5A214V mice, urinary Ca was not elevated. Despite an abnormal serum 1,25(OH)2D3 response to low dietary Ca, intestinal markers of Ca absorption (Trpv6, S100g mRNA) were elevated in Lrp5A214V mice and responded to low Ca intake. Collectively, our data indicate that the Lrp5A214V mutation induces changes in Ca homeostasis that permit mice to retain more Ca and support their high bone mass phenotype.
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Lay Summary
Optimizing peak bone mass (PBM) is critical for strong bones and osteoporosis prevention. Both genetics and dietary factors like calcium (Ca) contribute to PBM. The goal of this research study was to determine how dietary Ca intake and genetics interact with each other to impact bone mass. Lowering dietary Ca in control mice causes hormonal changes that increase intestinal Ca absorption and reduce urinary Ca loss to protect bone; but this process fails when dietary Ca becomes too low. However, mice with genetically programmed high bone mass could maintain high bone mass even when challenged with Ca deficient diets. This protection is because the high bone mass mice maintain higher serum Ca, have altered production and utilization of Ca-regulating hormones, and have increased molecular indicators of intestinal Ca absorption and kidney Ca retention. Our findings are important because they demonstrate how a genetic program that increases bone formation can drive improved efficiency of Ca utilization to accommodate the increased need for Ca deposition into bone. We believe that our preclinical study provides important proof-of-principle support for the concept of personalized recommendations for bone health management.
Wnt/β-catenin/LRPs, PTH/Vit D/FGF23, NUTRITION, Bone QCT/μCT, Genetic Animal Models
© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)
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