Abstract
The vitamin D receptor (VDR) knockout (KO) mouse is a common model to unravel novel metabolic functions of vitamin D. It is recommended to feed these mice a high calcium (2%), high phosphorus (1.25%) diet, termed rescue diet (RD) to prevent hypocalcaemia and secondary hyperparathyroidism. First, we characterized the individual response of VDR KO mice to feeding a RD and found that the RD was not capable of normalizing the parathyroid hormone (PTH) concentrations in each VDR KO mouse. In a second study, we aimed to study whether RD with additional 1 and 2% calcium (in total 3 and 4% of the diet) is able to prevent secondary hyperparathyroidism in the VDR KO mice. Wild type (WT) mice and VDR KO mice that received a normal calcium and phosphorus diet (ND) served as controls. Data demonstrated that the RD was no more efficient than the ND in normalizing PTH levels. An excessive dietary calcium concentration of 4% was required to reduce serum PTH concentrations in the VDR KO mice to PTH levels measured in WT mice. This diet, however, resulted in higher concentrations of circulating intact fibroblast growth factor 23 (iFGF23). To conclude, the commonly used RD is not suitable to normalize the serum PTH in VDR KO mice. Extremely high dietary calcium concentrations are necessary to prevent secondary hyperthyroidism in these mice, with the consequence that iFGF23 concentrations are being raised. Considering that PTH and iFGF23 exert numerous VDR independent effects, data obtained from VDR KO mice cannot be attributed solely to vitamin D.
Highlights
The vitamin D receptor (VDR) knockout (KO) mouse is an often used model to study the role of vitamin D in pathophysiological processes and for disease prevention
To elucidate the necessity and efficiency of this diet to normalize the mineral status and the serum parathyroid hormone (PTH) concentrations, we first characterized the individual response of VDR KO mice to feeding the classical rescue diet (RD) with 2% calcium and 1.25% phosphorus
We found that the mean concentration of circulating serum PTH in VDR KO was significantly higher than that of wild type (WT) mice placed on the same diet (Figure 1A)
Summary
The vitamin D receptor (VDR) knockout (KO) mouse is an often used model to study the role of vitamin D in pathophysiological processes and for disease prevention. Independent of the VDR KO mouse strain, some data indicated that it is possible to prevent secondary hyperparathyroidism by feeding the RD (Li et al, 1998; Kaneko et al, 2011), while other and own data showed that VDR KO mice fed the RD had extremely high concentrations of circulating PTH when compared with WT mice (Song et al, 2003; Shiizaki et al, 2009; Kühne et al, 2016). Own data obtained from VDR KO mice (Boston strain) demonstrated marked differences in the individual response of VDR KO mice to the RD (Kühne et al, 2016) These data raised doubts as to whether the RD is an appropriate diet to normalize, in particular, the PTH serum concentrations in each VDR KO mouse. Most published data of VDR KO mouse studies did not provide any information on circulating concentrations of PTH (Rummens et al, 2003; Simpson et al, 2007; Chen et al, 2015; Sakai et al, 2015)
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