Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Zachary C. Ryan, Hemamalini Ketha, Melissa S. McNulty, Meghan Elizabeth McGee Lawrence, Theodore A. Craig, Joseph P. Grande, Jennifer J. Westendorf, Ravinder J. Singh, Rajiv Kumar

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 phosphorusin micein 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.

Original languageEnglish (US)
Pages (from-to)6199-6204
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number15
DOIs
StatePublished - Apr 9 2013
Externally publishedYes

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Knockout Mice
Vitamin D
Calcium
Serum
Galactosidases
Physiologic Calcification
Bone Density
Phosphorus
Minerals
Hormones
Osteocytes
Messenger RNA
Lac Operon
Dihydroxycholecalciferols
Sclerosis
Osteoclasts
Mixed Function Oxygenases
Parathyroid Hormone
Osteoblasts
Osteogenesis

ASJC Scopus subject areas

  • General

Cite this

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. / Ryan, Zachary C.; Ketha, Hemamalini; McNulty, Melissa S.; McGee Lawrence, Meghan Elizabeth; Craig, Theodore A.; Grande, Joseph P.; Westendorf, Jennifer J.; Singh, Ravinder J.; Kumar, Rajiv.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 15, 09.04.2013, p. 6199-6204.

Research output: Contribution to journalArticle

Ryan, Zachary C. ; Ketha, Hemamalini ; McNulty, Melissa S. ; McGee Lawrence, Meghan Elizabeth ; Craig, Theodore A. ; Grande, Joseph P. ; Westendorf, Jennifer J. ; Singh, Ravinder J. ; Kumar, Rajiv. / Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 15. pp. 6199-6204.
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AB - 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 phosphorusin micein 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.

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