Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow

Takeshi Shibata, Ayako Shira-Ishi, Takuya Sato, Toshimi Masaki, Aya Sasaki, Yoshiko Masuda, Akinori Hishiya, Nobuyuki Ishikura, Sayumi Higashi, Yasuhiro Uchida, Moto O. Saito, Masako Ito, Etsuro Ogata, Ken Watanabe, Kyoji Ikeda

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1α,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.

Original languageEnglish
Pages (from-to)622-629
Number of pages8
JournalJournal of Bone and Mineral Research
Volume17
Issue number4
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Osteoclasts
Osteogenesis
Vitamin D
Bone Marrow
Hormones
Estrogens
Bone Resorption
Osteoporosis
Pharmacologic Actions
Bone and Bones
Macrophage Colony-Stimulating Factor
Calcitriol
Poisons
Prodrugs
Hypercalcemia
Cytoplasmic and Nuclear Receptors
Bone Marrow Cells
Ligands
alfacalcidol

Keywords

  • Alfacalcidol
  • Bone resorption
  • Osteoclasts
  • Osteoporosis
  • Ovariectomized mice
  • Receptor activator of nuclear factor κB ligand
  • Vitamin D

ASJC Scopus subject areas

  • Surgery

Cite this

Shibata, T., Shira-Ishi, A., Sato, T., Masaki, T., Sasaki, A., Masuda, Y., ... Ikeda, K. (2002). Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow. Journal of Bone and Mineral Research, 17(4), 622-629.

Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow. / Shibata, Takeshi; Shira-Ishi, Ayako; Sato, Takuya; Masaki, Toshimi; Sasaki, Aya; Masuda, Yoshiko; Hishiya, Akinori; Ishikura, Nobuyuki; Higashi, Sayumi; Uchida, Yasuhiro; Saito, Moto O.; Ito, Masako; Ogata, Etsuro; Watanabe, Ken; Ikeda, Kyoji.

In: Journal of Bone and Mineral Research, Vol. 17, No. 4, 2002, p. 622-629.

Research output: Contribution to journalArticle

Shibata, T, Shira-Ishi, A, Sato, T, Masaki, T, Sasaki, A, Masuda, Y, Hishiya, A, Ishikura, N, Higashi, S, Uchida, Y, Saito, MO, Ito, M, Ogata, E, Watanabe, K & Ikeda, K 2002, 'Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow', Journal of Bone and Mineral Research, vol. 17, no. 4, pp. 622-629.
Shibata, Takeshi ; Shira-Ishi, Ayako ; Sato, Takuya ; Masaki, Toshimi ; Sasaki, Aya ; Masuda, Yoshiko ; Hishiya, Akinori ; Ishikura, Nobuyuki ; Higashi, Sayumi ; Uchida, Yasuhiro ; Saito, Moto O. ; Ito, Masako ; Ogata, Etsuro ; Watanabe, Ken ; Ikeda, Kyoji. / Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow. In: Journal of Bone and Mineral Research. 2002 ; Vol. 17, No. 4. pp. 622-629.
@article{0626625545ca455797cd38453532b757,
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 κB (NF-κB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1α,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.",
keywords = "Alfacalcidol, Bone resorption, Osteoclasts, Osteoporosis, Ovariectomized mice, Receptor activator of nuclear factor κB ligand, Vitamin D",
author = "Takeshi Shibata and Ayako Shira-Ishi and Takuya Sato and Toshimi Masaki and Aya Sasaki and Yoshiko Masuda and Akinori Hishiya and Nobuyuki Ishikura and Sayumi Higashi and Yasuhiro Uchida and Saito, {Moto O.} and Masako Ito and Etsuro Ogata and Ken Watanabe and Kyoji Ikeda",
year = "2002",
language = "English",
volume = "17",
pages = "622--629",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow

AU - Shibata, Takeshi

AU - Shira-Ishi, Ayako

AU - Sato, Takuya

AU - Masaki, Toshimi

AU - Sasaki, Aya

AU - Masuda, Yoshiko

AU - Hishiya, Akinori

AU - Ishikura, Nobuyuki

AU - Higashi, Sayumi

AU - Uchida, Yasuhiro

AU - Saito, Moto O.

AU - Ito, Masako

AU - Ogata, Etsuro

AU - Watanabe, Ken

AU - Ikeda, Kyoji

PY - 2002

Y1 - 2002

N2 - Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1α,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.

AB - Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1α,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.

KW - Alfacalcidol

KW - Bone resorption

KW - Osteoclasts

KW - Osteoporosis

KW - Ovariectomized mice

KW - Receptor activator of nuclear factor κB ligand

KW - Vitamin D

UR - http://www.scopus.com/inward/record.url?scp=0036130689&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036130689&partnerID=8YFLogxK

M3 - Article

C2 - 11918219

AN - SCOPUS:0036130689

VL - 17

SP - 622

EP - 629

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 4

ER -