1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression.
1-Alpha, 25-dihydroxy vitamin D(3) (1alpha,25(OH)(2)D(3)), an active form of vitamin D(3), plays a critical role in calcium and bone metabolism. Although 1alpha,25(OH)(2)D(3) has been used for osteoporosis therapy, the direct role of 1alpha,25(OH)(2)D(3) on human osteoclastogenesis has not been well characterized. Here we show that 1alpha,25(OH)(2)D(3) treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1alpha,25(OH)(2)D(3) inhibited the expression of nuclear factor of activated T cells c1 (NFATc1, also referred as NFAT2), an essential transcription factor for osteoclast differentiation, and upregulated the expression of interferon-beta (IFN-beta), a strong inhibitor of osteoclastogenesis in osteoclast progenitors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on osteoclastogenesis and NFATc1 expression were restored by treatment with an antibody against IFN-beta, suggesting that upregulation of IFN-beta by 1alpha,25(OH)(2)D(3) treatment results in inhibition of NFATc1 expression, in turn interfering with osteoclast formation. Thus, our study may provide a molecular basis for the treatment of human bone diseases by 1alpha,25(OH)(2)D(3) through regulation of the IFN-beta and NFATc1 axis.
Sakai
Sadaoki
S
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Takaishi
Hironari
H
Matsuzaki
Kenichiro
K
Kaneko
Hironori
H
Furukawa
Mitsuru
M
Miyauchi
Yoshiteru
Y
Shiraishi
Ayako
A
Saito
Keiji
K
Tanaka
Akio
A
Taniguchi
Tadatsugu
T
Suda
Toshio
T
Miyamoto
Takeshi
T
Toyama
Yoshiaki
Y
D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism
D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053245:RANK Ligand; D016899:Interferon-beta; D002117:Calcitriol; D002118:Calcium