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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Arthritis, Experimental / immunology
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Arthritis, Experimental / metabolism
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Arthritis, Experimental / pathology
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Bone Resorption / immunology
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Bone Resorption / metabolism*
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Bone and Bones / cytology
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Bone and Bones / metabolism*
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Bone and Bones / pathology
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Carrier Proteins / metabolism
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Cell Differentiation / physiology
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Cells, Cultured
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I-kappa B Proteins / antagonists & inhibitors*
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Inflammation / immunology
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Inflammation / metabolism*
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Interleukin-1 / metabolism
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Macrophages / cytology
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Macrophages / metabolism
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Male
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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Osteoclasts / physiology*
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Peptides / metabolism*
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Signal Transduction / physiology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Carrier Proteins
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I-kappa B Proteins
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Interleukin-1
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Membrane Glycoproteins
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NF-kappa B
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Peptides
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Tumor Necrosis Factor-alpha