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Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines

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Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines This information is current as Masanobu Ohishi, Yumiko Matsumura, Daisuke Aki, of September 27, 2021. Ryuichi Mashima, Koji Taniguchi, Takashi Kobayashi, Toshio Kukita, Yukihide Iwamoto and Akihiko Yoshimura J Immunol 2005; 174:3024-3031; ; doi: 10.4049/jimmunol.174.5.3024 http://www.jimmunol.org/content/174/5/3024 Downloaded from References This article cites 35 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/174/5/3024.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines1 Masanobu Ohishi,*† Yumiko Matsumura,* Daisuke Aki,* Ryuichi Mashima,* Koji Taniguchi,* Takashi Kobayashi,* Toshio Kukita,‡ Yukihide Iwamoto,† and Akihiko Yoshimura2* Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physio- logical roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-␥-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deficient BMMs, but was diminished in SOCS1-overex- ؉ ؊ pressing BMMs. Moreover, LPS-induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1 / mice Downloaded from compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-␥ on osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and I␬B were drastically reduced and receptor activator of the NF-␬B ligand-induced I␬B phosphorylation was severely impaired in the presence of IL-6. These data http://www.jimmunol.org/ suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-␬B ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction. The Journal of Immunology, 2005, 174: 3024–3031. balance between bone resorption and bone formation by osteoprotegerin ligand (7), produced by activated T cells stimu- bone-resorbing osteoclasts and bone-forming osteo- lates its cognate receptor, RANK, expressed on osteoclast A blasts is critical for the maintenance of bone strength and precursors (8). RANKL, a member of the TNF family, is essential by guest on September 27, 2021 integrity (1). Hyperactivation and/or accumulation of osteoclasts for the differentiation of monocyte/macrophage precursors to os- cause bone destruction in pathological conditions, such as autoim- teoclasts (9). Binding of RANKL to its receptor, RANK, results in mune arthritis, periodontitis, postmenopausal osteoporosis, Paget’s the recruitment of the TNF-receptor-associated factor (TRAF) disease, and bone tumors (2, 3). Enhanced osteoclastic bone re- family of proteins, including TRAF6, which is an essential adapter sorption causes severe bone damage, leading to progressive joint molecule for osteoclastogenesis, leading to the activation of destruction in autoimmune arthritis, in which receptor activator of NF-␬B and JNK (9). In addition, RANKL induces the expression 3 the NF-␬B ligand (RANKL), (4) also known as TNF-related ac- of c-Fos, an essential transcription factor for osteoclastogenesis, by tivation-induced cytokine (5)/osteoclast differentiation factor (6)/ an unknown mechanism (10). A recent study by Takayanagi et al. (11) demonstrated that IFN-␥ secreted from activated T cells counterbalances the action *Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, †Department of Orthopedic Surgery, Faculty of Medicine, and ‡Oral Cellular and of RANKL, which contributes to maintaining bone homeostasis. Molecular Biology, Department of Oral Biological Sciences, Faculty of Dental Sci- Moreover, it was demonstrated that IFN-␤ inhibits osteoclastogen- ences, Kyushu University, Fukuoka, Japan esis by interfering with the RANKL-induced expression of c-Fos Received for publication August 31, 2004. Accepted for publication December (10). IFN-␥ is shown to induce ubiquitination and proteasomal 13, 2004. degradation of TRAF6 (11), whereas IFN-␤ induces the suppres- 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 sion of c-Fos expression by a posttranscriptional control mecha- with 18 U.S.C. Section 1734 solely to indicate this fact. nism(s) (10). Therefore, the modulation of RANK signaling by 1 This work was supported by special grants-in-aid from the Ministry of Education, inflammatory cytokines is important for bone remodeling to main- Science, Technology, Sports, and Culture of Japan; the Takeda Science Foundation; tain bone homeostasis in both physiologic and pathologic states. the Kato Memorial Trust for Nanbyo Research; the Haraguchi Memorial Foundation; the Yamanoucih Foundation for Research on Metabolic Disorders; and the Uehara How IFN-␥ induces degradation of TRAF6 and how IFN-␤ in- Memorial Foundation. duces c-Fos reduction remain to be determined. 2 Address correspondence and reprint requests to Dr. Akihiko Yoshimura, Division of IFNs use the JAK/STAT pathways for their signal transduction Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu Uni- (12). A group of cytokine-inducible factors, the suppressor of cy- versity, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: [email protected] tokine signaling (SOCS) family, which mediate negative feedback 3 Abbreviations used in this paper: RANKL, receptor activator of NF-␬B ligand; mechanisms of cytokine signaling by inhibiting the JAK/STAT BMM, bone marrow-derived monocyte; IRES, internal ribosomal entry site; KO, pathway, has recently been discovered (12). Among them, SOCS1 knockout; MNC, multinuclear cell; RANK, receptor activator of NF-␬B; SOCS, sup- pressor of cytokine signaling; TRAF, TNF receptor-associated factor; TRAP, tartrate- and SOCS3, negative feedback regulators for STAT1 and STAT3 resistant acid phosphatase; WT, wild type. pathways, respectively, inhibit JAK tyrosine kinase activity in Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 3025 slightly different manners; SOCS1 directly binds to the activation Retroviral gene transduction loop of JAKs through the Src homology 2 domain, whereas We constructed a retrovirus vector carrying SOCS1 and SOCS3 cDNA SOCS3 directly binds to cytokine receptors, including gp130, a with an internal ribosomal entry site (IRES)-enhanced GFP (pMX-SOCS1/ signal transducer of IL-6-related cytokines. The Src homology 2 SOCS3-IRES-EGFP). pMX-IRES-EGFP (empty) was used as a control domain of SOCS3 has been shown to bind to Y757 of gp130, vector. Retrovirus packaging was performed as previously described (25). which is also known as a binding site for the protein tyrosine Bone marrow cells obtained from 5- to 8-wk-old ddy mice were cultured for 24 h in the presence of M-CSF (R&D Systems; 100 ng/ml). Cells were phosphatase 2 (Src homology 2 domain-containing phosphatase-1) vigorously washed by pipetting, and adherent cells were incubated in a (13). These two molecules contain a similar kinase inhibitor region virus stock medium containing polybrene (Roche) at 4 ␮g/ml for 4 h. at the N terminus, which is essential for JAK inhibition (13). Anal- Infected cells were cultured for 2 days in the presence of M-CSF (100 ysis of SOCS1- and SOCS3-deficient macrophages indicated that ng/ml) and subjected to in vitro osteoclastogenesis. SOCS1 negatively regulates the IFNs/STAT1 (12) as well as TLR In vitro osteoclastogenesis
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