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J. Biol. Chem., Vol. 279, Issue 36, 37219-37222, September 3, 2004

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The IB Kinase (IKK) Inhibitor, NEMO-binding Domain Peptide, Blocks Osteoclastogenesis and Bone Erosion in Inflammatory Arthritis^*

Simon Dai, Teruhisa Hirayama, Sabiha Abbas, and Yousef Abu-Amer

From the Department of Orthopaedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Activation of NF-B leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses. The process is facilitated by induction of IB kinase (IKK) complex that phosphorylates IB and leads to its dissociation from the NF-B complex, thus permitting activation of NF-B. The IKK complex contains primarily IKK, IKK, and the regulatory kinase IKK, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKK and IKK, 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-B. Given the pivotal role of cytokine-induced NF-B 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-B and inhibits cytokine-induced osteoclast formation by osteoclast precursors. Consistent with the key role of NF-B 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.

Received for publication, June 3, 2004 , and in revised form, June 29, 2004.

^* This work was supported in part by National Institutes of Health Grants DE-13754, AR-47443, and AR-049192 (to Y. A.-A.), an arthritis investigator award (to Y. A.-A.), and a grant from the Shriners Hospital for Children (to Y. A.-A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Washington University School of Medicine, Dept. of Orthopedic Surgery, One Barnes Hospital Plaza, 11300 West Pavilion, Campus Box 8233, St. Louis, MO 63110. Tel.: 314-362-0335; Fax: 314-362-0334; E-mail: abuamery{at}msnotes.wustl.edu.

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