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

Eijiro Jimi, Kazuhiro Aoki, Hiroaki Saito, Fulvio D'Acquisto, Michael J May, Ichiro Nakamura, Testuo Sudo, Takefumi Kojima, Fujio Okamoto, Hidefumi Fukushima, Koji Okabe, Keiichi Ohya, Sankar Ghosh

Research output: Contribution to journalArticlepeer-review


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-kappa B (NF-kappa B) has a crucial role in osteoclast differentiation, and blocking NF-kappa B is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the I kappa B-kinase complex, a crucial component of signal transduction pathways to NF-kappa B. The peptide inhibited RANKL-stimulated NF-kappa B 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-alpha and interleukin-1 beta, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-kappa B activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption.

Original languageEnglish
Pages (from-to)617-24
Number of pages8
JournalNature Medicine
Issue number6
Publication statusPublished - Jun 2004


  • Animals
  • Arthritis, Experimental
  • Bone Marrow Cells
  • Bone Resorption
  • Bone and Bones
  • Carrier Proteins
  • Cell Differentiation
  • Cells, Cultured
  • I-kappa B Proteins
  • Inflammation
  • Interleukin-1
  • Macrophages
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • NF-kappa B
  • Osteoclasts
  • Peptides
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Signal Transduction
  • Tumor Necrosis Factor-alpha
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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