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

• Published in: The Journal of biological chemistry 2002-08, Vol.277 (31), p.27880-27886
• Main Authors: Hayashi, Toshikichi, Kaneda, Toshio, Toyama, Yoshiaki, Kumegawa, Masayoshi, Hakeda, Yoshiyuki
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - cytology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation - physiology; Cell Nucleus - physiology; DNA-Binding Proteins - metabolism; Gene Expression Regulation - physiology; Hematopoietic Stem Cells - cytology; Humans; Interferon Type I - genetics; Interferon-beta - physiology; Intracellular Signaling Peptides and Proteins; Macrophage Colony-Stimulating Factor - pharmacology; Membrane Glycoproteins - metabolism; Mice; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - physiology; Phosphorylation; Proteins - genetics; Proteins - metabolism; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Recombinant Proteins - pharmacology; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; STAT1 Transcription Factor; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators - metabolism; Transcription Factors
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M203836200

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 microenvironments. 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.