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B Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos1
* Department of Orthopaedic Surgery,
Department of Pathology, and
Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan; and
Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27R
(WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-
B ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-B ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.
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.
1 This work was supported in part by Teijin Pharma and by Grant-in-Aid for Young Scientists (B) 20791055.
2 Address correspondence and reprint requests to Dr. Hironari Takaishi, Department of Orthopaedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: hironari{at}sc.itc.keio.ac.jp
3 Abbreviations used in this paper: MNC, multinucleated cell; BM, bone marrow; BMM, bone marrow macrophage; EBI3, EBV-induced gene 3; ECW, E. coli cell wall lysate; GM, granulocyte-macrophage; gp130, IL-6 signal transducer; h, human; microCT, micro-computed tomography; m, mouse; NFATc1, cytoplasmic, calcineurin-dependent 1 NFAT; RANK, receptor activator of NF-B; RANKL, RANK ligand; SCF, stem cell factor; TRAF, TNFR-associated factor; TRAP, tartrate-resistant acid phosphatase; WSX-1, IL-27R; siRNA, small interference RNA; WT, wild type.
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