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.
Jimi
Eijiro
E
Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Aoki
Kazuhiro
K
Saito
Hiroaki
H
D'Acquisto
Fulvio
F
May
Michael J
MJ
Nakamura
Ichiro
I
Sudo
Testuo
T
Kojima
Takefumi
T
Okamoto
Fujio
F
Fukushima
Hidefumi
H
Okabe
Koji
K
Ohya
Keiichi
K
Ghosh
Sankar
S
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism*; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002352:Carrier Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha