1
Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
2
Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
3
Department of Orthopedic Surgery, Yugawara Kosei-nenkin Hospital, Kanagawa 259-0314, Japan.
4
Basic Research Laboratories, Toray Industries, Incorporated, Kamakura 248-0036, Japan.
5
Section of Cellular Physiology, Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
6
Present address: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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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B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo
B (NF-
and interleukin-1
, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-
