title: Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow.
abstract: Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1alpha,25-dihydroxyvitamin D3 [1a,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1alpha,25(OH)2D3, suppresses bone resorption at pharmacologic doses that maintain normocalcemia in an ovariectomized (OVX) mouse model of osteoporosis. Treatment of OVX mice with pharmacologic doses of alfacalcidol does not increase RANKL expression, whereas toxic doses that cause hypercalcemia markedly reduce the expression of RANKL. When bone marrow (BM) cells from OVX mice were cultured with sufficient amounts of macrophage colony-stimulating factor (M-CSF) and RANKL, osteoclastogenic activity was higher than in sham mice. Marrow cultures from alfacalcidol- or estrogen-treated OVX mice showed significantly less osteoclastogenic potential compared with those from vehicle-treated OVX mice, suggesting that the pool of osteoclast progenitors in the marrow of vitamin D-treated mice as well as estrogen-treated mice was decreased. Frequency analysis showed that the number of osteoclast progenitors in bone marrow was increased by OVX and decreased by in vivo treatment with alfacalcidol or estrogen. We conclude that the pharmacologic action of active vitamin D in vivo is to decrease the pool of osteoclast progenitors in BM, thereby inhibiting bone resorption. Because of its unusual activity of maintaining bone formation while suppressing bone resorption, in contrast to estrogens that depress both processes, vitamin D hormone and its bone-selective analogs may be useful for the management of osteoporosis.
authors.affiliation: Department of Geriatric Research, National Institute for Longevity Sciences, Aichi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shibata
authors.forename: Ayako
authors.initials: A
authors.lastname: Shira-Ishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Sato
authors.forename: Toshimi
authors.initials: T
authors.lastname: Masaki
authors.forename: AyaSasakiYoshiko
authors.initials: A
authors.lastname: Masuda
authors.forename: Akinori
authors.initials: A
authors.lastname: Hishiya
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishikura
authors.forename: Sayumi
authors.initials: S
authors.lastname: Higashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Moto-O
authors.initials: MO
authors.lastname: Saito
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ogata
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D001862:Bone Resorption; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006887:Hydroxycholecalciferols / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D010024:Osteoporosis / Q000188:drug therapy; D010052:Ovariectomy; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013234:Stem Cells / Q000187:drug effects*; D014807:Vitamin D / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D006887:Hydroxycholecalciferols; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014807:Vitamin D; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor; C008088:alfacalcidol