Regulation of receptor activator of NF-κB ligand-induced osteoclastogenesis by endogenous interferon-β (INF-β) and suppressors of cytokine signaling (SOCS) -: The possible counteracting role of SOCSs in IFN-β-inhibited osteoclast formation

被引:78
作者
Hayashi, T
Kaneda, T
Toyama, Y
Kumegawa, M
Hakeda, Y [1 ]
机构
[1] Meikai Univ, Sch Dent, Dept Oral Anat, Sakado, Saitama 3500283, Japan
[2] Keio Univ, Sch Med, Dept Orthopaed Surg, Tokyo 1608582, Japan
[3] Hoshi Univ, Fac Pharmaceut Sci, Dept Pathophysiol, Tokyo 1428501, Japan
关键词
D O I
10.1074/jbc.M203836200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Bone resorption and the immune system are correlated with each other, and both are controlled by a variety of common cytokines produced in the bone micro-environments. Among these immune mediators, the involvement of type I interferons (IFNs) in osteoclastic bone resorption remains unknown. In this study, we investigated the participation of IFN-beta and suppressors of cytokine signaling (SOCS)-1 and -3 in osteoclastogenesis. Addition of exogenous IFN-beta to osteoclast progenitors (bone-derived monocytes/macrophages) inhibited their differentiation toward osteoclasts induced by the receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor with/without transforming growth factor-beta, where inhibition was associated with down-regulation of the gene expressions of molecules related to osteoclast differentiation. In addition, RANKL induced the expression of IFN-beta; furthermore, neutralizing antibody against type I IFNs accelerated the osteoclast formation, indicating type I IFNs as potential intrinsic inhibitors. On the other hand, RANKL also induced the expression of SOCS-1 and -3, suppressors of the IFN signaling. Pretreatment with RANKL for a sufficient time for the induction of SOCSs attenuated phosphorylation of STAT-1 in response to IFN-beta in osteoclast progenitors, causing a decrease in the binding activity of nuclear extracts toward the interferon-stimulated response element. mRNA levels of STAT-1, STAT-2, and IFN-stimulated gene factor-3gamma, comprising IFN-stimulated gene factor-3, were not altered by RANKL. Thus, although the inhibitory cytokine such as IFN-beta is produced in response to RANKL, the inhibition of osteoclastogenesis may be rescued by the induction of signaling suppressors such as SOCSs.
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页码:27880 / 27886
页数:7
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