The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis.
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.
Miyauchi
Yoshiteru
Y
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Ninomiya
Ken
K
Miyamoto
Hiroya
H
Sakamoto
Akemi
A
Iwasaki
Ryotaro
R
Hoshi
Hiroko
H
Miyamoto
Kana
K
Hao
Wu
W
Yoshida
Shigeyuki
S
Morioka
Hideo
H
Chiba
Kazuhiro
K
Kato
Shigeaki
S
Tokuhisa
Takeshi
T
Saitou
Mitinori
M
Toyama
Yoshiaki
Y
Suda
Toshio
T
Miyamoto
Takeshi
T
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*
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