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  • Phosphorylation of the p Rel A dimer the most


    Phosphorylation of the p50-Rel A dimer, the most common form of NF-κB, leads to ubiquitination of IκB proteins (Fig. 2). Poly-ubiquitination of IκB proteins identifies them for rapid degradation by 26S proteasomes, thereby allowing NF-κB dimers to undergo nuclear translocation and activate the transcription of various target pyruvate dehydrogenase kinase inhibitor [95]. However, prior to their degradation, the phosphorylation of IκB proteins by the IκB kinase (IKK) complex facilitates NF-κB activation. The IKK complex consists of a regulatory component, IKKγ or NF-κB essential modulator (NEMO), and catalytic subunits (IKKα and IKKβ) [95], [96], [97], [98]. In MRL/lpr mice, phosphorylation of IκBα, an endogenous inhibitory molecule of NF-κB activation and nuclear translocation of the p50 and p65 subunits of NF-κB, is significantly enhanced compared with control mice [65], [99]. These results suggest that osteoclast activation which occurs with RA involves a role for the classical pathway of NF-κB activation (Fig. 2). Correspondingly, in both in vivo and in vitro studies a cell-permeable peptide spanning a NEMO-binding domain has been shown to inhibit osteoclastogenesis and activation of NF-κB induced by RANKL [88]. Therefore, it is proposed that a potential strategy for preventing osteoclastogenesis and effectively treating the inflammation associated with bone resorption is to selectively inhibit NF-κB in osteoclasts [65], [88].
    Blocking nuclear translocation of NF-κB in osteoclasts as therapeutic target of RA Different strategies have been proposed and tested to inhibit the activation or function of NF-κB. One approach has employed decoy NF-κB sites or their analogs to interfere with the binding of NF-κB to DNA [100]. However, such molecules are polar and rather large, thereby potentially hindering their uptake and cellular bioavailability [96]. Conversely, considering the large interaction surface between NF-κB and DNA, it may be difficult for non-polar molecules that are small in size to specifically disrupt the binding of NF-κB to DNA [96]. A similar argument could be made for molecules designed to inhibit NF-κB protein dimerization [96], [101]. Alternatively, it has been proposed that small peptides that can readily cross the cell membrane could inhibit the activation of NF-κB by blocking translocation of the NF-κB complex to the nucleus. This approach was tested by generating a synthetic peptide that contains the nuclear localization sequence of the p50 NF-κB subunit and a hydrophobic region to facilitate translocation across a cell membrane. This peptide, named SN50, was shown to competitively inhibit the nuclear translocation of NF-κB (Fig. 2) [96], [100], [102]. Moreover, both in vivo and in vitro, SN50 was found to effectively inhibit TNF-α and lipopolysaccharide (LPS)-induced inflammatory responses [102]. SN50 has also been shown to block the translocation of many other transcriptional factors to the nucleus, and to abrogate activation of caspase-3 [96], [100], [103], [104]. In mice, administration of SN50 effectively suppressed NF-κB activation that was dependent on TNF-α/JNK signaling [105], as well as MMP production in alveolar macrophages [106]. Furthermore, in resting normal human peripheral blood derived T cells, the addition of SN50 abolished osteoclast differentiation and induced apoptosis [107], [108]. Based on the results presented here, blocking nuclear translocation of the p50 NF-κB subunit appears to be an effective approach for attenuating the number of osteoclasts present and reducing expression of Sphk1 and S1P1. In particular, it has recently been demonstrated that SN50 targeting of p50 NF-κB translocation to the nuclei of bone marrow macrophages (BMMs) in RA model of MRL/lpr mice inhibits RANKL-induced osteoclastogenesis (Fig. 2) [65]. Subchondral trabecular bone loss in the mandibular condyle was also ameliorated, and this was accompanied by lower expression levels of the osteoclast marker, TRAP, as well as cathepsin K, vascular endothelial growth factor (VEGF), MMP-9, and RANKL. Moreover, treatment with SN50 increased expression of OPG and reduced Sphk1 expression and S1P1 signaling [65]. Taken together, these findings suggest that SN50 is an effective inhibitor of osteoclastogenesis and the preceding migration of osteoclast precursor cells.