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(The FASEB Journal. 2002;16:274-282.)
© 2002 FASEB

CpG oligonucleotides: novel regulators of osteoclast differentiation

WEI ZOU, HARRY SCHWARTZ, STEFAN ENDRES*, GUNTHER HARTMANN* and ZVI BAR-SHAVIT1

The H. Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel; and
* Division of Clinical Pharmacology, Department of Medicine Ludwig-Maximilians-University, 80336 Munich, Germany

1Correspondence: The H. Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, P.O. Box 12272, Jerusalem 91120, Israel. E-mail: barsha{at}cc.huji.ac.il

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-{kappa}B activation in murine macrophages. In light of the pivotal role played by NF-{kappa}B 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 1ß (IL-1ß) 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.—Zou, W., Schwartz, H., Endres, S., Hartmann, G., Bar-Shavit, Z. CpG oligonucleotides: novel regulators of osteoclast differentiation.


Key Words: RANKL • TNF-{alpha} • M-CSF • bone • immunostimulatory oligodexynucleotide




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