title: Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass.
abstract: Humans with mutations of the sclerostin (SOST) gene, and knockout animals in which the Sost gene has been experimentally deleted, exhibit an increase in bone mass. We review the mechanisms by which Sost knockout mice are able to accrete increased amounts of calcium and phosphorus required for the maintenance of a high bone mass. Recently published information from our laboratory, shows that bone mass is increased in Sost-deficient mice through an increase in osteoblast and a decrease in osteoclast activity, which is mediated by activation of β-catenin and an increase in prostacyclin synthesis in osteocytes and osteoblasts. The increases in calcium and phosphorus retention required for enhanced bone mineral accretion are brought about by changes in the vitamin D endocrine system, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Thus, in Sost knockout mice, concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) are increased and concentrations of FGF-23 are decreased thereby allowing a positive calcium and phosphorus balance. Additionally, in the absence of Sost expression, urinary calcium is decreased, either through a direct effect of sclerostin on renal calcium handling, or through its effect on the synthesis of 1,25(OH)2D. Adaptations in vitamin D, PTH and FGF-23 physiology occur in the absence of sclerostin expression and mediate increased calcium and phosphorus retention required for the increase in bone mineralization. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA; Department of Internal Medicine, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905 USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Ryan
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA; Department of Internal Medicine, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905 USA.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Craig
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: McGee-Lawrence
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA; Department of Internal Medicine, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905 USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st St., SW, Rochester, MN 55905, USA. Electronic address: rkumar@mayo.edu.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism*; D014815:Vitamins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; C486030:Sost protein, mouse; D014815:Vitamins; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: 1,25(OH)(2)D; Cyp27b1; FGF-23; PTH; Sclerostin; Urinary calcium