TY - JOUR
T1 - CpG oligonucleotides
T2 - Novel regulators of osteoclast differentiation
AU - Zou, W. E.I.
AU - Schwartz, Harry
AU - Endres, Stefan
AU - Hartmann, Gunther
AU - Bar-Shavit, Z. V.I.
PY - 2002
Y1 - 2002
N2 - 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-κB activation in murine macrophages. In light of the pivotal role played by NF-κB 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-pre-treated BMMs. CpG ODN enhanced the expression of interleukin 1β (IL-1β) and tumor necrosis factor (TNF-α). Antibodies to TNF-α 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-α, 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.
AB - 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-κB activation in murine macrophages. In light of the pivotal role played by NF-κB 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-pre-treated BMMs. CpG ODN enhanced the expression of interleukin 1β (IL-1β) and tumor necrosis factor (TNF-α). Antibodies to TNF-α 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-α, 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.
KW - Bone
KW - Immunostimulatory oligodexynucleotide
KW - M-CSF
KW - RANKL
KW - TNF-α
UR - http://www.scopus.com/inward/record.url?scp=0036190385&partnerID=8YFLogxK
U2 - 10.1096/fj.01-0586com
DO - 10.1096/fj.01-0586com
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C2 - 11874977
AN - SCOPUS:0036190385
SN - 0892-6638
VL - 16
SP - 274
EP - 282
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -