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Although both an active form of the vitamin D metabolite, 1,25(OH) 2 D 3 , 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) 2 D 3  -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) 2 D 3 , suppress HIF1α protein expression in osteoclasts  in vitro . We found that 1,25(OH) 2 D 3  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) 2 D 3   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) 2 D 3   in vitro , were both significantly higher following treatment with 1,25(OH) 2 D 3  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) 2 D 3 , could be a reliable read-out in either developing or screening reagents targeting osteoporosis.

The Vitamin D Analogue ED71 but Not 1,25(OH)2D3 Targets HIF1α Protein in Osteoclasts