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Article
Nature Medicine 10, 617 - 624 (2004)
Published online: 23 May 2004 | doi:10.1038/nm1054
Selective inhibition of NF-
B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo
Eijiro Jimi1,5, Kazuhiro Aoki2, Hiroaki Saito2, Fulvio D'Acquisto1, Michael J May1,6, Ichiro Nakamura3, Testuo Sudo4, Takefumi Kojima2, Fujio Okamoto5, Hidefumi Fukushima5, Koji Okabe5, Keiichi Ohya2 & Sankar Ghosh1
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-
B (NF-B) has a crucial role in osteoclast differentiation, and blocking NF-B is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the IB-kinase complex, a crucial component of signal transduction pathways to NF-B. The peptide inhibited RANKL-stimulated NF-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-
and interleukin-1
, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-B activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption.
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