title: The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis.
abstract: Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets 'osteoclastic' molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1-Bcl6-osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Ken
authors.initials: K
authors.lastname: Ninomiya
authors.forename: Hiroya
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hoshi
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yoshida
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Mitinori
authors.initials: M
authors.lastname: Saitou
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006132:Growth Plate / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D010006:Osteoblasts / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C490010:Bcl6 protein, mouse; C499636:DC-STAMP protein, mouse; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; C534132:Ctsk protein, mouse