BoneKEy Reports | BoneKEy Watch

Sclerostin could regulate vitamin D metabolism and calcium excretion

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DOI:10.1038/bonekey.2013.172

Ryan et al. generated a strain of mice in which the gene encoding sclerostin (Sost) was replaced by the gene encoding β-D-galactosidase (lacZ) to investigate how mutations that inactivate SOST lead to enhanced bone mineralization.

Activity of the lacZ gene was detected in the osteocytes of the knockout mice, confirming a successful gene replacement. As expected, the Sost−/− mice showed increased osteoblast surfaces, reduced osteoclast surfaces and enhanced net bone formation. Compared to wild-type mice, they also had higher levels of serum 1α,25-dihydroxyvitamin D (1α,25(OH)2D)—the active metabolite of vitamin D—and lower levels of 24,25-dihydroxyvitamin D (the inactive metabolite).

The authors suggest that this could be related to the lower levels of intact fibroblast growth factor 23 (FGF-23) detected in the serum of the Sost−/− mice. They hypothesize that sclerostin could have a direct effect on expression of Cyp27b1, the gene encoding 25-hydroxyvitamin D 1α-hydroxylase cytochrome P450, in the proximal tubules of the kidney.

Editor’s comment: By generating a novel strain of sost knockout mice and carefully examining calcium/phosphate homeostasis, the authors of this study have made a hugely surprising discovery: sclerostin potentially regulates FGF-23 and thereby controls 1α-hydroxylase and 1α,25(OH)2 D levels. Since such alterations have not been reported in previous strains, in transgenic models or in humans harboring sclerosteosis or VanBuchem mutations, their actual significance is still to be established.

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