Enhanced inhibitory effects of a novel CpG motif on osteoclast differentiation via TREM-2 down-regulation.

Abstract:

:Recognition of oligodeoxynucleotides containing CpG motifs (CpG-ODNs) by toll-like receptor 9 (TLR9) inhibits RANKL-induced osteoclastogenesis from precursors. This inhibitory effect suggests the possibility of using this strategy to block pathological bone loss. However, the enhancing effect of CpG-ODNs on OC formation from RANKL-primed pre-osteoclasts (pOCs) has hampered their clinical use. In this report, we developed a CpG-KSK13 oligonucleotide with an alternative CpG motif, and tested its effect on osteoclastogenesis in comparison with previously used murine CpG motif (CpG-1826) or human CpG motif (CpG-2006) oligonucleotides. Murine CpG-1826 inhibited RANKL-induced OC formation from BMMs but not from RANKL-primed pOCs, while CpG-KSK13 treatment strongly inhibited OC formation from both BMM and primed pOC cells. CpG-KSK13 also showed a potent inhibitory effect on human OC differentiation using peripheral blood mononuclear cells (PBMCs), which was in contrast to the species-specific response of murine CpG-1826 or human CpG-2006. Moreover, CpG-KSK13 effectively inhibited NFATc1 activity, but not NF-kappaB or AP-1 activity, and decreased TREM-2 promoter activity and subsequent surface expression of the TREM-2 protein induced by M-CSF and RANKL. These results demonstrate that the recognition of CpG-KSK13 via TLR9 inhibits osteoclastogenesis by down-regulating TREM-2 expression. Thus, our findings provide evidence for the potential use of CpG-KSK13 as an anti-osteoclastogenic agent for human and for pre-clinical animals.

authors

Chang JH,Chang EJ,Kim HH,Kim SK

doi

10.1016/j.bbrc.2009.08.080

subject

Has Abstract

pub_date

2009-11-06 00:00:00

pages

28-33

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(09)01656-8

journal_volume

389

pub_type

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