CpG oligonucleotides: novel regulators of osteoclast differentiation

FASEB J. 2002 Mar;16(3):274-82. doi: 10.1096/fj.01-0586com.

Abstract

The macrophage capability to recognize bacterial DNA is mimicked by oligodeoxynucleotides containing unmethylated CG dinucleotides ('CpG' motifs) in specific sequence contexts (CpG ODN). CpG ODN stimulates NF-kappaB activation in murine macrophages. In light of the pivotal role played by NF-kappaB in osteoclast differentiation, we examined the ability of CpG ODN to modulate osteoclastogenesis. CpG ODN alone induced TRAP-positive cells in bone marrow macrophage (BMM) cultures, but not multinucleation or calcitonin receptor expression. CpG ODN inhibited RANKL-induced osteoclastogenesis when present from the beginning of BMM culture, but strongly increased RANKL-induced osteoclastogenesis in RANKL-pretreated BMMs. CpG ODN enhanced the expression of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). Antibodies to TNF-alpha and the TNF type 1 receptor, but not the addition of IL-1 receptor antagonist, blocked CpG ODN-induced osteoclastogenesis in RANKL-pretreated cultures. On the other hand, CpG ODN reduced expression of the M-CSF receptor, which is critical during the initiation of osteoclast differentiation. These results suggest that CpG ODN, via the induction of TNF-alpha, support osteoclastogenesis in cells that are committed to the osteoclast differentiation pathway but, due to down-modulation of M-CSF receptor, inhibit early steps of osteoclast differentiation. Thus, CpG ODN represents a potential therapeutic tool for treating bone diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / analysis
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antibodies / pharmacology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / pharmacology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Dose-Response Relationship, Drug
  • Isoenzymes / analysis
  • Kinetics
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / physiology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Oligodeoxyribonucleotides / pharmacology*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • RANK Ligand
  • RNA, Messenger / biosynthesis
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptor, Macrophage Colony-Stimulating Factor / biosynthesis
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / physiology
  • Tartrate-Resistant Acid Phosphatase
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Adjuvants, Immunologic
  • Antibodies
  • CPG-oligonucleotide
  • Carrier Proteins
  • Cytokines
  • Isoenzymes
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • RANK Ligand
  • RNA, Messenger
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Receptor, Macrophage Colony-Stimulating Factor
  • Acid Phosphatase
  • Acp5 protein, mouse
  • Tartrate-Resistant Acid Phosphatase