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-κB 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.
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2009 Nov 6|
Bibliographical noteFunding Information:
We thank H. Takayanagi (Tokyo Medical and Dental University, JAPAN) for providing the OSCAR and TREM-2 promoter-dependent reporter plasmids. This work was supported by Grants from the 21C Frontier Functional Proteomics Project (FPR08B1-170) and Science Research Center ( R11-2008-023-01001-0 ) to H.H. Kim, and from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0920020) to S.K. Kim. E.J. Chang was supported, in part, by the Korea Research Foundation Grant funded by MEST ( KRF-2007-359-E00001 ).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology