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

Nature Medicine volume 10, pages 617–624 (2004)Cite this article

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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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.

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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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Author notes

  1. Michael J May

    Present address: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

Authors and Affiliations

  1. Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Eijiro Jimi, Fulvio D'Acquisto, Michael J May & Sankar Ghosh

  2. Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan

    Kazuhiro Aoki, Hiroaki Saito, Takefumi Kojima & Keiichi Ohya

  3. Department of Orthopedic Surgery, Yugawara Kosei-nenkin Hospital, Kanagawa, 259-0314, Japan

    Ichiro Nakamura

  4. Basic Research Laboratories, Toray Industries, Incorporated, Kamakura, 248-0036, Japan

    Testuo Sudo

  5. Department of Physiological Science and Molecular Biology, Section of Cellular Physiology, Fukuoka Dental College, Fukuoka, 814-0193, Japan

    Eijiro Jimi, Fujio Okamoto, Hidefumi Fukushima & Koji Okabe

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Correspondence to Sankar Ghosh.

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Jimi, E., Aoki, K., Saito, H. et al. Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med 10, 617–624 (2004). https://doi.org/10.1038/nm1054

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