title: Bcl6 promotes osteoblastogenesis through Stat1 inhibition.
abstract: Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Funayama
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Miyauchi
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
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: Kanagawa
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Tando
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanaji
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: miyamoto@z5.keio.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D004247:DNA
keywords: Bcl6; Bone; Differentiation; Osteoblast; Stat1