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

Abstract

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.

• Authors: Hisashi Takasu, Atsuko Sugita, Yasushi Uchiyama, Nobuyoshi Katagiri, Makoto Okazaki, Etsuro Ogata, Kyoji Ikeda
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 2 Pg. 528-35 (Feb 2006) ISSN: 0021-9738 [Print] United States
• PMID: 16424941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Density Conservation Agents
• Carrier Proteins
• Glycoproteins
• Membrane Glycoproteins
• Osteoprotegerin
• Proto-Oncogene Proteins c-fos
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Receptors, Calcitriol
• Receptors, Cytoplasmic and Nuclear
• Receptors, Tumor Necrosis Factor
• Tnfrsf11a protein, mouse
• Tnfrsf11b protein, mouse
• Tnfsf11 protein, mouse
• Calcitriol

Topics

• Animals
• Bone Density Conservation Agents (metabolism, therapeutic use)
• Bone Resorption (prevention & control)
• Calcitriol (analogs & derivatives, metabolism, therapeutic use)
• Carrier Proteins (metabolism)
• Cell Differentiation (physiology)
• Female
• Glycoproteins (genetics, metabolism)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoporosis (drug therapy, metabolism)
• Osteoprotegerin
• Ovariectomy
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Receptors, Calcitriol (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Receptors, Tumor Necrosis Factor (genetics, metabolism)
• Signal Transduction (physiology)
• Stem Cells (cytology, metabolism)