title: CpG oligonucleotides: novel regulators of osteoclast differentiation.
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.
authors.affiliation: The H. Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Harry
authors.initials: H
authors.lastname: Schwartz
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Zvi
authors.initials: Z
authors.lastname: Bar-Shavit
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000032:analysis; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; C408982:CPG-oligonucleotide; D002352:Carrier Proteins; D016207:Cytokines; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase