Selective inhibition of NF-[kappa]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-[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.
Author(s): Eijiro Jimi [1, 5]; Kazuhiro Aoki [2]; Hiroaki Saito [2]; Fulvio D'Acquisto [1]; Michael J May [1, 6]; Ichiro Nakamura [3]; Testuo Sudo [4]; Takefumi Kojima [2]; Fujio Okamoto [...]