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5588.Full.Pdf Protein Inhibitor of Activated STAT 3 Modulates Osteoclastogenesis by Down-Regulation of NFATc1 and Osteoclast-Associated Receptor This information is current as of October 2, 2021. Kabsun Kim, Junwon Lee, Jung Ha Kim, Hye Mi Jin, Bin Zhou, Soo Young Lee and Nacksung Kim J Immunol 2007; 178:5588-5594; ; doi: 10.4049/jimmunol.178.9.5588 http://www.jimmunol.org/content/178/9/5588 Downloaded from References This article cites 39 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/178/9/5588.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 October 2, 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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Protein Inhibitor of Activated STAT 3 Modulates Osteoclastogenesis by Down-Regulation of NFATc1 and Osteoclast-Associated Receptor1 Kabsun Kim,2* Junwon Lee,2* Jung Ha Kim,* Hye Mi Jin,* Bin Zhou,† Soo Young Lee,‡ and Nacksung Kim3* Protein inhibitor of activated STAT3 (PIAS3) has been shown to regulate the activity of various transcription factors. In this study, we show that the overexpression of PIAS3 in bone marrow-derived monocyte/macrophage lineage cells attenuates osteoclast formation and down-regulates the expression of NFATc1 and osteoclast-associated receptor (OSCAR), which are important modulators in osteoclastogenesis. PIAS3 has been shown to associate with histone deacetylase 1 as well as with transcription factors, including the microphthalmia transcription factor, NFATc1, and c-Fos. Moreover, overexpression of PIAS3 inhibits the transactivation of target genes such as NFATc1 and OSCAR. This inhibitory effect of PIAS3 is possibly mediated by histone Downloaded from deacetylase 1 recruitment to the promoter regions of NFATc1 and OSCAR. Furthermore, silencing of PIAS3 by RNA interference in osteoclast precursors enhances osteoclast formation as well as gene expression of NFATc1 and OSCAR. Taken together, our results reveal that PIAS3 acts as a modulator in osteoclastogenesis. The Journal of Immunology, 2007, 178: 5588–5594. eceptor activator of NF-␬B ligand (RANKL4; also called oclast-associated receptor (OSCAR) is a member of the Ig-like TRANCE, OPGL, and ODF) induces osteoclast forma- surface receptor family and plays an important role as a costimu- http://www.jimmunol.org/ R tion from monocyte/macrophage precursors of hemopoi- latory receptor for osteoclast differentiation by activating NFATc1 etic origin (1–3). The binding of RANKL to its receptor, receptor through association with the FcR␥-chain (8, 11–13). In addition, activator of NF-␬B (RANK), activates NF-␬B, JNK, p38, ERK, NFATc1 synergistically induces OSCAR gene expression with and AKT, which are important for the differentiation, activation, Mitf and PU.1 (14, 15). Therefore, a positive feedback circuit in- and survival of osteoclasts (4, 5). RANKL activates and/or induces volving RANKL, NFATc1, and OSCAR appears to be important the expression of transcription factors known to be important for for the efficient differentiation of osteoclasts (14, 16). osteoclastogenesis in vitro and in vivo including c-Fos, microph- The mammalian protein inhibitor of activated STAT (PIAS) thalmia transcription factor (Mitf), PU.1, and NFATc1 (5–7). Co- family consists of PIAS1, PIAS3, PIASx, and PIASy, and the by guest on October 2, 2021 stimulatory signals mediated by ITAM-harboring adaptors, includ- PIAS proteins were initially identified as negative regulators of ing DNAX-activating protein 12 (DAP12) and FcR␥, cooperate STAT signaling (17, 18). Later, a role for PIAS in regulating the with RANKL for osteoclastogenesis, and their activation enhances activity of transcription factors, including NF-␬B, the SMA- and the induction of NFATc1 via calcium signaling (8–10). Oste- MAD-related proteins (SMADs), and tumor suppressor p53 has been proposed (19, 20). Although PIAS proteins act chiefly as repressors of transcription, they have been shown to be positive *Research Institute of Medical Sciences and Medical Research Center for Gene Reg- regulators of transcription as well (19). Recent studies have dem- ulation, Chonnam National University Medical School, Gwangju, Korea; †Depart- ment of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232; onstrated that PIAS proteins contain a small ubiquitin-like modi- and ‡Division of Molecular Life Science and Center for Cell Signaling Research, fier (SUMO) with ligase activity (19, 21). SUMO modification Ewha Woman University, Seoul, Korea proceeds by a three-step enzyme shuttle analogous to ubiquitina- Received for publication November 13, 2006. Accepted for publication February tion (22). SUMO modification appears to play an important role in 7, 2007. targeting proteins to specific subnuclear structures, stabilizing The costs of publication of this article were defrayed in part by the payment of page target proteins, and regulating the transcriptional activity of charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. substrate proteins (22). However, it has also been suggested that 1 This work was supported in part by Korea Research Foundation Grant KRF-2005- PIAS proteins induce transcriptional repression independently 015-E00152 and Grant R13-2002-013-03001-0 from the Korea Science and Engi- of SUMO ligase activity by recruiting other corepressors such neering Foundation through the Medical Research Center for Gene Regulation at as histone deacetylases (HDACs) to the promoter region of their Chonnam National University. target genes (20, 23). 2 K.K. and J.L. contributed equally to this work. Mitf, a basic helix-loop-helix zipper protein, plays a key regu- 3 Address correspondence and reprint requests to Dr. Nacksung Kim, Medical Re- search Center for Gene Regulation, Chonnam National University Medical School, latory role in several cell types such as mast cells, melanocytes, Hak-Dong 5, Dong-Ku, Gwangju, Korea. E-mail address: [email protected] and osteoclasts. Mitf regulates the expression of various genes, 4 Abbreviations used in this paper: RANKL, receptor activator of nuclear factor ␬B including mast cell protease 6, OSCAR, and cathepsin K (15, 24). ligand; BMM, bone marrow-derived macrophage-like cell; ChIP, chromatin immu- The mice with mutations at the mi locus develop severe osteope- noprecipitation; HDAC, histone deacetylase; Luc, luciferase; Mitf, microphthalmia transcription factor; MNC, multinuclear osteoclast; OSCAR, osteoclast-associated re- trosis due to defective osteoclasts (25, 26), suggesting a key role ceptor; PIAS, protein inhibitor of activated STAT; SUMO, small ubiquitin-like mod- for Mitf in osteoclastogenesis. Recently, PIAS3 has been shown to ifier; siRNA, small interference RNA; TRAP, tartrate-resistant acid phosphatase; HA, suppress Mitf transcriptional activity by blocking its DNA binding hemagglutinin. domain, leading to the intriguing possibility that PIAS3 may play Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 a key role in the regulation of bone remodeling (27). It has been www.jimmunol.org The Journal of Immunology 5589 shown that PIAS proteins regulate cell cycle, apoptosis, and im- Western blot analysis mune responses in many cell types, but the role of PIAS3 in os- Cells from transfected 293T, BMMs, or osteoclasts were harvested after teoclast differentiation has yet to be determined. washing with ice-cold PBS and then lysed in extraction buffer (50 mM We report here that overexpression of PIAS3 in osteoclast pre- Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 0.5% Nonidet P-40, and cursors inhibits osteoclast formation and attenuates the expression 0.01% protease inhibitor mixture). Immunoprecipitated samples with the of NFATc1 and OSCAR during osteoclastogenesis. This inhibi- indicated Abs or whole cell lysates were subjected to SDS-PAGE and Western blotting. Primary Abs used included c-Fos (Calbiochem), tory effect of PIAS3 is mediated by the recruitment of HDAC1, a NFATc1 (BD Pharmingen), OSCAR (12), actin, Flag (Sigma-Aldrich), and corepressor protein, to the promoter regions of NFATc1 and HA (Roche). HRP-conjugated secondary Abs (Amersham Biosciences) OSCAR. Moreover, the silencing of PIAS3 by RNA interference were probed and developed with ECL solution (Amersham Biosciences). induces the expression of NFATc1 and OSCAR as well as en- Signals were detected and analyzed by LAS3000 luminescent image ana- lyzer (Fuji Photo Film). hances osteoclast differentiation. Thus, this study shows that PIAS3 may play an important role in RANKL-mediated Transfection and luciferase assay osteoclastogenesis. For transfection of reporter plasmids, 293T cells were plated on 24-well plates at a density of 3 ϫ 104 cells/well
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