title: NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation.
abstract: BACKGROUND
  Monocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved.
  
  
  RESULTS
  In this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-κB) in the regulation of these miRNAs, as well as with their targets, whereby NF-κB p65 binds the promoters of these two miRNA clusters and NF-κB inhibition or depletion results in impaired upregulation of their expression.
  
  
  CONCLUSIONS
  Our results reveal the direct involvement of NF-κB in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: de la Rica
authors.forename: Antonio
authors.initials: A
authors.lastname: García-Gómez
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Comet
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Ubreva
authors.forename: Laura
authors.initials: L
authors.lastname: Ciudad
authors.forename: Roser
authors.initials: R
authors.lastname: Vento-Tormo
authors.forename: Carlos
authors.initials: C
authors.lastname: Company
authors.forename: Damiana
authors.initials: D
authors.lastname: Álvarez-Errico
authors.forename: Mireia
authors.initials: M
authors.lastname: García
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Vaquero
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D005810:Multigene Family; D016328:NF-kappa B / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger; D015533:Transcriptional Activation
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger