Abstract
Activation of NF-kappaB leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses. The process is facilitated by induction of IkappaB kinase (IKK) complex that phosphorylates IkappaB and leads to its dissociation from the NF-kappaB complex, thus permitting activation of NF-kappaB. The IKK complex contains primarily IKKalpha, IKKbeta, and the regulatory kinase IKKgamma, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKKalpha and IKKbeta, 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-kappaB. Given the pivotal role of cytokine-induced NF-kappaB 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-kappaB and inhibits cytokine-induced osteoclast formation by osteoclast precursors. Consistent with the key role of NF-kappaB 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.
Highlights
From the Department of Orthopaedics and Cell Biology & Physiology, Washington University School of Medicine, St
Consistent with the key role of NF-B in osteoinflammatory responses in vivo, wild type TAT-NEMO-binding domain (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
Wild Type NBD Peptide Inhibits IKK and NF-B Activation in OCPs—IKK induction is essential for phosphorylation of IB and subsequent activation of NF-B
Summary
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. It was shown recently that IKK␣ catalytic activity is required for RANKL-induced NF-B activation in mammary epithelial cells [17] and B-lymphocytes [18] These mechanisms were associated with the non-classical (non-canonical) NF-B activation pathway, namely targeting the NF-B2/p100 to process p52NF-B [19]. These observations strongly suggest that IKK␣ and IKK are prone to execute distinct signaling pathways based on the nature of their own activation This activation of the IKKs is tightly regulated by the non-catalytic IKK␥/NEMO [14, 20]. NEMO may facilitate the recruitment of upstream IKK activators such as kinases that target the activation loops within the catalytic domains of the IKK subunits [22]
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