The vitamin D analogue ED71 but Not 1,25(OH)2D3 targets HIF1α protein in osteoclasts.
Although both an active form of the vitamin D metabolite, 1,25(OH)2D3, and the vitamin D analogue, ED71 have been used to treat osteoporosis, anti-bone resorbing activity is reportedly seen only in ED71- but not in 1,25(OH)2D3 -treated patients. In addition, how ED71 inhibits osteoclast activity in patients has not been fully characterized. Recently, HIF1α expression in osteoclasts was demonstrated to be required for development of post-menopausal osteoporosis. Here we show that ED71 but not 1,25(OH)2D3, suppress HIF1α protein expression in osteoclasts in vitro. We found that 1,25(OH)2D3 or ED71 function in osteoclasts requires the vitamin D receptor (VDR). ED71 was significantly less effective in inhibiting M-CSF and RANKL-stimulated osteoclastogenesis than was 1,25(OH)2D3 in vitro. Downregulation of c-Fos protein and induction of Ifnβ mRNA in osteoclasts, both of which reportedly block osteoclastogenesis induced by 1,25(OH)2D3 in vitro, were both significantly higher following treatment with 1,25(OH)2D3 than with ED71. Thus, suppression of HIF1α protein activity in osteoclasts in vitro, which is more efficiently achieved by ED71 rather than by 1,25(OH)2D3, could be a reliable read-out in either developing or screening reagents targeting osteoporosis.
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Yuiko
Y
Sato
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Yoshiteru
Y
Miyauchi
Department of Dentistry and Oral Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Shigeyuki
S
Yoshida
Department of Dentistry and Oral Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Mayu
M
Morita
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Tami
T
Kobayashi
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Hiroya
H
Kanagawa
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Eri
E
Katsuyama
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Atsuhiro
A
Fujie
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Wu
W
Hao
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Toshimi
T
Tando
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Ryuichi
R
Watanabe
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Kana
K
Miyamoto
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Hideo
H
Morioka
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Morio
M
Matsumoto
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Yoshiaki
Y
Toyama
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Takeshi
T
Miyamoto
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives; D014815:Vitamins / Q000494:pharmacology*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018167:Receptors, Calcitriol; D014815:Vitamins; D014807:Vitamin D; D002117:Calcitriol; C547512:eldecalcitol