1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression

1-Alpha, 25-dihydroxy vitamin D-3 (1 alpha,25(OH)(2)D-3), an active form of vitamin D-3, plays a critical role in calcium and bone metabolism. Although 1 alpha,25(OH)(2)D-3 has been used for osteoporosis therapy, the direct role of 1 alpha,25(OH)(2)D-3 on human osteoclastogenesis has not been well characterized. Here we show that 1 alpha,25(OH)(2)D-3 treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1 alpha,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 1 alpha,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 1 alpha,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 1 alpha,25(OH)(2)D-3 through regulation of the IFN-beta and NFATc1 axis.