The IκB Kinase (IKK) Inhibitor, NEMO-binding Domain Peptide, Blocks Osteoclastogenesis and Bone Erosion in Inflammatory Arthritis
Activation of NF-κB leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses. The process is facilitated by induction of IκB kinase (IKK) complex that phosphorylates IκB and leads to its dissociation from the NF-κB complex, thus permitting activation of NF-κB...
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Published in | The Journal of biological chemistry Vol. 279; no. 36; p. 37219 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
03.09.2004
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Online Access | Get full text |
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Summary: | Activation of NF-κB leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses. The process
is facilitated by induction of IκB kinase (IKK) complex that phosphorylates IκB and leads to its dissociation from the NF-κB
complex, thus permitting activation of NF-κB. The IKK complex contains primarily IKKα, IKKβ, and the regulatory kinase IKKγ,
also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKKα and IKKβ,
termed NEMO-binding domain (NBD). In this regard, a cell-permeable NBD peptide has been shown to block association of NEMO
with the IKK complex and inhibit activation of NF-κB. Given the pivotal role of cytokine-induced NF-κB in osteoclastogenesis
and inflammatory bone loss, we deduced that cell-permeable TAT-NBD peptide may hinder osteoclastogenesis and bone erosion
in inflammatory arthritis. Using NBD peptides, we show that wild type, but not mutant, NBD blocks IKK activation and reduces
cytokine-induced promoter and DNA binding activities of NF-κB and inhibits cytokine-induced osteoclast formation by osteoclast
precursors. Consistent with the key role of NF-κB in osteoinflammatory responses in vivo , wild type TAT-NBD administered into mice prior to induction of inflammatory arthritis efficiently block in vivo osteoclastogenesis, inhibits focal bone erosion, and ameliorates inflammatory responses in the joints of arthritic mice.
The mutant NBD peptide fails to exert these functions. These results provide strong evidence that IKKs are potent regulators
of cytokine-induced osteoclastogenesis and inflammatory arthritis. More importantly, blockade of NEMO assembly with the IKK
complex is a viable strategy to avert inflammatory osteolysis. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.C400258200 |