Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo
- 23 May 2004
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 10 (6), 617-624
- https://doi.org/10.1038/nm1054
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.Keywords
This publication has 39 references indexed in Scilit:
- Inhibition of NF-κB by a TAT-NEMO–binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosisBlood, 2003
- RANKL and RANK as novel therapeutic targets for arthritisCurrent Opinion in Rheumatology, 2003
- Osteoclast differentiation and activationNature, 2003
- Characterization of the IκB-kinase NEMO Binding DomainPublished by Elsevier BV ,2002
- Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammationBritish Journal of Pharmacology, 2002
- Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclastsJCI Insight, 1999
- Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and ActivationCell, 1998
- Requirement for NF-κB in osteoclast and B-cell developmentGenes & Development, 1997
- Collagen-induced arthritis, an animal model of autoimmunityLife Sciences, 1997
- Identification of osteoclasts and their mononuclear precursors. A comparative histological and histochemical study in hamster periodontitisJournal of Periodontal Research, 1991