Selective inhibition of NF-κB 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

421 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)617-624
Number of pages8
JournalNature Medicine
Volume10
Issue number6
DOIs
Publication statusPublished - 2004 Jun

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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