Blimp1-mediated repression of negative regulators is required for osteoclast differentiation.
Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-kappaB ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed. However, it has been unclear how such negative regulators are repressed during osteoclastogenesis. Here we show that B lymphocyte-induced maturation protein-1 (Blimp1; encoded by Prdm1), which is induced by RANKL through NFATc1 during osteoclastogenesis, functions as a transcriptional repressor of anti-osteoclastogenic genes such as Irf8 and Mafb. Overexpression of Blimp1 leads to an increase in osteoclast formation, and Prdm1-deficient osteoclast precursor cells do not undergo osteoclast differentiation efficiently. The importance of Blimp1 in bone homeostasis is underscored by the observation that mice with an osteoclast-specific deficiency in the Prdm1 gene exhibit a high bone mass phenotype caused by a decreased number of osteoclasts. Thus, NFATc1 choreographs the determination of cell fate in the osteoclast lineage by inducing the repression of negative regulators as well as through its effect on positive regulators.
Nishikawa
Keizo
K
Department of Cell Signaling, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
Nakashima
Tomoki
T
Hayashi
Mikihito
M
Fukunaga
Takanobu
T
Kato
Shigeaki
S
Kodama
Tatsuhiko
T
Takahashi
Satoru
S
Calame
Kathryn
K
Takayanagi
Hiroshi
H
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051258:MafB Transcription Factor / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology; D016133:Polymerase Chain Reaction; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D017931:DNA Primers; D050835:Interferon Regulatory Factors; D051258:MafB Transcription Factor; D050778:NFATC Transcription Factors; D009841:Oligonucleotides; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053245:RANK Ligand; D012097:Repressor Proteins; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C490406:Mafb protein, mouse; C513258:Prdm1 protein, mouse; C505689:Tnfsf11 protein, mouse