Department of Nutritional Sciences, University of Texas, Austin, TX 78723, United States.
Department of Physical Therapy, Indiana University -Purdue University, Indianapolis, IN 46202, United States.
J Bone Miner Res. 2024 Apr 19;39(3):315-325. doi: 10.1093/jbmr/zjae011.
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.
环境因素和遗传变异单独影响骨骼。然而，目前尚不清楚这些因素如何相互作用影响峰值骨量的积累。在这里，我们测试了由 Lrp5 基因（Lrp5A214V）中的错义突变驱动的遗传编程的高骨形成是否改变了小鼠对饮食钙（Ca）摄入不足环境的敏感性。我们在断奶后用 AIN-93G 饮食喂养 Lrp5A214V 雄性小鼠和野生型同窝仔（对照），饮食中的 Ca 含量分别为 0.125%、0.25%、0.5%（参考，基础）或 1%，直到 12 周龄（即骨骼生长期间）。分析了尿钙、血清钙、钙调节激素（PTH、1,25 二羟维生素 D3（1,25(OH)2D3））、骨参数（μCT、灰分）和肾/肠基因表达。正如预期的那样，低饮食 Ca 摄入对骨骼产生负面影响，而 Lrp5A214V 小鼠的骨量和灰分含量更高。尽管 Lrp5A214V 小鼠的骨骼有更多的基质要矿化，但它们的骨骼对低饮食 Ca 摄入并不更敏感。在对照小鼠中，低饮食 Ca 摄入对血清 Ca（降低）、PTH（增加）和 1,25(OH)2D3（增加）及其下游作用（即减少尿钙，增加肠 Ca 吸收标志物）产生预期影响。相比之下，Lrp5A214V 小鼠血清 Ca 升高，PTH 反应正常，但 1,25(OH)2D3 对低饮食 Ca 的反应减弱，这反映在肾脏 1,25(OH)2D3 产生/降解酶 Cyp27b1 和 Cyp24a1 中。尽管 Lrp5A214V 小鼠血清 Ca 升高，但尿钙未升高。尽管对低饮食 Ca 的血清 1,25(OH)2D3 反应异常，但 Lrp5A214V 小鼠的肠 Ca 吸收标志物（Trpv6、S100g mRNA）升高，并对低 Ca 摄入有反应。总的来说，我们的数据表明，Lrp5A214V 突变诱导 Ca 稳态的变化，使小鼠保留更多的 Ca 并支持其高骨量表型。
