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

J Clin Invest. 2006 Feb;116(2):528-35. doi: 10.1172/JCI24742. Epub 2006 Jan 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density Conservation Agents / metabolism*
  • Bone Density Conservation Agents / therapeutic use
  • Bone Resorption / prevention & control
  • Calcitriol / analogs & derivatives*
  • Calcitriol / metabolism*
  • Calcitriol / therapeutic use
  • Carrier Proteins / metabolism
  • Cell Differentiation / physiology
  • Female
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoporosis / drug therapy
  • Osteoporosis / metabolism
  • Osteoprotegerin
  • Ovariectomy
  • 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

Substances

  • 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