High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice

Abstract

25-hydroxyvitamin D (25OH D) 1α-hydroxylase (CYP27B1) knockout (KO) mice are growth retarded, hypocalcemic, and have osteomalacia. This can be prevented by 1,25 dihydroxyvitamin D (1,25 D) injections or by feeding a 2% calcium (Ca), 20% lactose rescue diet. We tested whether high dietary vitamin D3 (VD) could exert biological effects in the absence of CYP27B1 in vivo. Male weanling KO and wild-type (WT) mice were randomized to the rescue diet or AIN93G diets (0.5% Ca, 0.4% phosphorus) with 1,000 (1K, the rodent requirement), 10,000 (10K) or 20,000 (20K) IU VD/kg diet. Growth and food intake were monitored until 12 weeks of age, at which time blood and tissues were taken. Serum 25OH D was >500 nM (10 fold elevated) in mice fed the 10K and 20K IU VD diets. Serum 1,25 D was at the limit of detection in KO mice and did not increase when 25OH D was elevated by diet. While KO mice on the 1,000 IU diet displayed impaired growth and hypocalcemia, both the 10K and 20K IU VD diets were as effective as the rescue diet in promoting growth and normalizing serum Ca. In KO mice, high dietary VD also restored calbindin D9K gene expression in intestine and kidney and normalized bone parameters as assessed by microCT scanning. These data demonstrate that high serum 25OH D can regulate calcium and bone metabolism independent of its conversion to 1,25 D. This work was supported by NIH CA10113 (JCF), DK054111 (JCF) CA103018, (JW), and CA69700 (JW).