The Vitamin D Analogue ED71 but Not 1,25(OH)(2)D(3) Targets HIF1α Protein in Osteoclasts

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.