c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs
| Autor: | Yasushi Uchiyama, Kyoji Ikeda, Nobuyoshi Katagiri, Hisashi Takasu, Makoto Okazaki, Atsuko Sugita, Etsuro Ogata |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Calcitriol Ovariectomy Receptors Cytoplasmic and Nuclear Biology Calcitriol receptor Receptors Tumor Necrosis Factor Bone resorption Mice Osteoprotegerin Osteoclast Internal medicine Bone cell medicine Animals Bone Resorption Glycoproteins Mice Knockout Membrane Glycoproteins Bone Density Conservation Agents Receptor Activator of Nuclear Factor-kappa B Stem Cells RANK Ligand Cell Differentiation General Medicine Mice Inbred C57BL medicine.anatomical_structure Endocrinology RANKL biology.protein Osteoporosis Receptors Calcitriol Female Carrier Proteins Proto-Oncogene Proteins c-fos Signal Transduction Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 116:528-535 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci24742 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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