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

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 I?B-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-a and interleukin-1ß, 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. [ABSTRACT FROM AUTHOR]