c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs

• Published in: The Journal of clinical investigation 2006-02, Vol.116 (2), p.528-535
• Main Authors: Takasu, Hisashi, Sugita, Atsuko, Uchiyama, Yasushi, Katagiri, Nobuyoshi, Okazaki, Makoto, Ogata, Etsuro, Ikeda, Kyoji
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; Bone density; Bone Density Conservation Agents - metabolism; Bone Density Conservation Agents - therapeutic use; Bone marrow; Bone Resorption - prevention & control; Calcitriol - analogs & derivatives; Calcitriol - metabolism; Calcitriol - therapeutic use; Carrier Proteins - metabolism; Cell Differentiation - physiology; Cytokines; Drug dosages; Estrogens; Female; Glycoproteins - genetics; Glycoproteins - metabolism; Kinases; Ligands; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Oral administration; Osteoporosis; Osteoporosis - drug therapy; Osteoporosis - metabolism; Osteoprotegerin; Ovariectomy; Proteins; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction - physiology; Stem Cells - cytology; Stem Cells - metabolism; Vitamin D
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci24742

Although active vitamin D drugs have been used for the treatment of osteoporosis, how the vitamin D receptor (VDR) regulates bone cell function remains largely unknown. Using osteoprotegerin-deficient mice, which exhibit severe osteoporosis due to excessive receptor activator of NF-kappaB ligand/receptor activator of NF-kappaB (RANKL/RANK) stimulation, we show herein that oral treatment of these mice with 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] inhibited bone resorption and prevented bone loss, suggesting that VDR counters RANKL/RANK signaling. In M-CSF-dependent osteoclast precursor cells isolated from mouse bone marrow, 1alpha,25(OH)2D3 potently and dose-dependently inhibited their differentiation into multinucleate osteoclasts induced by RANKL. Among signaling molecules downstream of RANK, 1alpha,25(OH)2D3 inhibited the induction of c-Fos protein after RANKL stimulation, and retroviral expression of c-Fos protein abrogated the suppressive effect of 1alpha,25(OH)2D3 on osteoclast development. By screening vitamin D analogs based on their c-Fos-suppressing activity, we identified a new analog, named DD281, that inhibited bone resorption and prevented bone loss in ovariectomized mice, more potently than 1alpha,25(OH)2D3, with similar levels of calcium absorption. Thus, c-Fos protein is an important target of the skeletal action of VDR-based drugs, and DD281 is a bone-selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity.