title: Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium.
abstract: Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin (sost) gene was replaced by the β-D-galactosidase (lacZ) gene in the germ line. Knockout (KO) (sost(-/-)) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 (cyp27B1) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.
authors.affiliation: Nephrology Research, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Ryan
authors.forename: Hemamalini
authors.initials: H
authors.lastname: Ketha
authors.forename: Melissa S
authors.initials: MS
authors.lastname: McNulty
authors.forename: Meghan
authors.initials: M
authors.lastname: McGee-Lawrence
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Craig
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.forename: Ravinder J
authors.initials: RJ
authors.lastname: Singh
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density; D002118:Calcium / Q000652:urine*; D002853:Chromatography, Liquid; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006023:Glycoproteins / Q000378:metabolism*; D006579:Heterozygote; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010011:Osteocytes / Q000166:cytology; D014807:Vitamin D / Q000097:blood*; D055114:X-Ray Microtomography; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D001616:beta-Galactosidase; D002118:Calcium