Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system.
J Bone Miner Res
; 39(3): 315-325, 2024 Apr 19.
Article
em En
| MEDLINE
| ID: mdl-38477773
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.
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cálcio da Dieta
/
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade
Limite:
Animals
Idioma:
En
Revista:
J Bone Miner Res
Ano de publicação:
2024
Tipo de documento:
Article