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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2202-2212. Prepublished online as a Blood First Edition Paper on October 24, 2008; DOI 10.1182/blood-2008-06-162594. This Article Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-06-162594v1 113/10/2202    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hikata, T. Articles by Toyama, Y. Search for Related Content PubMed PubMed Citation Articles by Hikata, T. Articles by Toyama, Y. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 13, 2008 Accepted October 6, 2008 PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts Tomohiro Hikata, Hironari Takaishi*, Jiro Takito, Akihiro Hakozaki, Mitsuru Furukawa, Shinichi Uchikawa, Tokuhiro Kimura, Yasunori Okada, Masahito Matsumoto, Akihiko Yoshimura, Riko Nishimura, Sakamuri V Reddy, Hiroshi Asahara, and Yoshiaki Toyama Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan Department of Pathology, School of Medicine, Keio University, Tokyo, Japan Department of Molecular Biology, Saitama Medical School, Saitama, Japan Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan Department of Molecular and Cellular Biochemistry, Osaka University, Osaka, Japan Children's Research Institute, Medical University of South Carolina, Charleston, SC, United States Department of Innovative Surgery, National Center for Child Health and Development, Tokyo, Japan * Corresponding author; email: hironari{at}sc.itc.keio.ac.jp. Cytokine signaling via various transcription factors regulates Receptor Activator of NF-B ligand (RANKL)-mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3, and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of MITF independent of sumoylation. Downregulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), downregulates RANKL expression induced by IL-6 cytokine family, and inhibits osteoclast formation from BMMs in vitro co-culture system. Downregulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and sIL-6R. Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Furukawa, H. Takaishi, J. Takito, M. Yoda, S. Sakai, T. Hikata, A. Hakozaki, S. Uchikawa, M. Matsumoto, K. Chiba, et al. IL-27 Abrogates Receptor Activator of NF-{kappa}B Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos J. Immunol., August 15, 2009; 183(4): 2397 - 2406. [Abstract] [Full Text] [PDF]

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