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-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 language | English |
|---|---|
| Pages (from-to) | 617-24 |
| Number of pages | 8 |
| Journal | Nature Medicine |
| Volume | 10 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2004 |
Keywords
- 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.