title: An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion.
abstract: Macrophage lineage cells such as osteoclasts and foreign body giant cells (FBGCs) form multinuclear cells by cell-cell fusion of mononuclear cells. Recently, we reported that two seven-transmembrane molecules, osteoclast stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP), were essential for osteoclast and FBGC cell-cell fusion in vivo and in vitro. However, signaling required to regulate FBGC fusion remained largely unknown. Here, we show that signal transducer and activator of transcription 1 (STAT1) deficiency in macrophages enhanced cell-cell fusion and elevated DC-STAMP expression in FBGCs. By contrast, lack of STAT6 increased STAT1 activation, significantly inhibiting cell-cell fusion and decreasing OC-STAMP and DC-STAMP expression in IL-4-induced FBGCs. Furthermore, either STAT1 loss or co-expression of OC-STAMP/DC-STAMP was sufficient to induce cell-cell fusion of FBGCs without IL-4. We conclude that the STAT6-STAT1 axis regulates OC-STAMP and DC-STAMP expression and governs fusogenic mechanisms in FBGCs.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hoshi
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kanagawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D002459:Cell Fusion; D005786:Gene Expression Regulation / Q000502:physiology; D015743:Giant Cells, Foreign-Body / Q000166:cytology / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C499636:DC-STAMP protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C527519:OC-STAMP protein, mouse; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015847:Interleukin-4