Mcgill J Med. 2009; 12(2): 11.
Sophia Biyao Xiao(1) and Dr. Karaplis(2)
1 – Marianopolis College, Montreal, Quebec, Canada
2 – Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia, and inappropriately low-normal serum concentration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. Much of our understanding of XLH came from the murine homolog, the Hyp mouse. The 25- hydroxyvitamin D-24-hydroxylase enzyme (CYP24) is responsible for the catabolic breakdown of 1,25 (OH)2D3. In this study, we sought to investigate the contribution of Cyp24 to the deranged vitamin D metabolism observed in Hyp mice. We bred male Hyp mice with female Cyp24 +/– mice to generate obligate heterozygotes in female mice, and then crossed female Cyp24 +/–/ Hyp mice (Phex+/-) with male Cyp24 +/– mice to obtain male Cyp24 -/-/ Hyp mice. Mice were sacrificed around 50 days post partum and serum and tissues were procured for analysis and comparison to controls. Genotyping of live animals around the time of weaning demonstrated that 75% of the double mutant animals died by 7 weeks of age. Serum calcium level in these animals was similar to that of the three control groups while serum inorganic phosphorous was as low as that in Hyp littermates. Serum parathyroid hormone (PTH) and 1,25(OH)2D3 levels were decreased similar to those in the Cyp24-/- littermates while on the other hand, circulating serum FGF23 levels and serum alkaline phosphatase activity were higher than in Hyp littermates. Importantly, ablation of Cyp24 restored the skeletal abnormalities associated with Hyp. These findings support the contention that the enzymatic activity of Cyp24 partakes in the pathogenetic mechanism of Hyp resulting in the profound rachitic alterations observed in these mice. Further research is currently underway to examine the effect of CYP24 on PTH regulation in vitro.
To whom correspondence should be addressed:
Sophia Biyao Xiao