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Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo

Abstract

Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis and periodontitis. Inflammation-induced bone loss of this sort results from elevated numbers of bone-resorbing osteoclasts. Gene targeting studies have shown that the transcription factor nuclear factor-κB (NF-κB) has a crucial role in osteoclast differentiation, and blocking NF-κB is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the IκB-kinase complex, a crucial component of signal transduction pathways to NF-κB. The peptide inhibited RANKL-stimulated NF-κB activation and osteoclastogenesis both in vitro and in vivo. In addition, this peptide significantly reduced the severity of collagen-induced arthritis in mice by reducing levels of tumor necrosis factor-α and interleukin-1β, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-κB activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption.

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Acknowledgements

This work was supported by the National Institutes of Health (R37-AI33443) and the Howard Hughes Medical Institute (S.G.), a Scientist Development Grant from the American Heart Association (M.J.M.), by Grants-in-Aid for Scientific Research (13557151) from the Ministry of Education, Culture, Sports Science and Technology of Japan (K.A.) and by the Takeda Science Foundation (E.J.).

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Correspondence to Sankar Ghosh.

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The authors declare no competing financial interests.

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Supplementary Methods (PDF 8 kb)

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Figure 1: NBD peptide inhibits RANKL-induced osteoclastogenesis in vitro.
Figure 2: Effects of the NBD peptides on osteoblast differentiation and function.
Figure 3: Inhibition of RANKL-induced osteoclastogenesis in vivo after injection of the NBD peptide.
Figure 4: The NBD peptide inhibits LPS-induced increases in the osteoclast precursor population in vivo.
Figure 5: The NBD peptide reduces inflammation and suppresses bone destruction in an experimental model of CIA.
Figure 6: The NBD peptide inhibits NF-κB activation and modulates pro- and anti-inflammatory gene expression in serum and tissues in CIA.