title: The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis.
abstract: OBJECTIVE
  MicroRNA, a class of noncoding RNA, play a role in human diseases. MicroRNA-146a (miR-146a) is a negative regulator of immune and inflammatory responses, and is strongly expressed in rheumatoid arthritis (RA) synovium and peripheral blood mononuclear cells (PBMCs). This study was undertaken to examine whether miR-146a expression inhibits osteoclastogenesis, and whether administration of miR-146a prevents joint destruction in mice with collagen-induced arthritis (CIA).
  
  
  METHODS
  PBMCs from healthy volunteers were isolated and seeded in culture plates. The following day, double-stranded miR-146a was transfected and cultured in the presence of macrophage colony-stimulating factor and either tumor necrosis factor α or RANKL. After 3 weeks, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells were counted. Three days after miR-146a culture, the expression of c-Jun, nuclear factor of activated T cells c1 (NF-ATc1), PU.1, and TRAP was evaluated by quantitative reverse transcriptase-polymerase chain reaction. After the onset of distinct arthritis in mice with CIA, double-stranded miR-146a or nonspecific double-stranded RNA was administered twice by intravenous injection. Radiographic and histologic examinations were performed at 4 weeks.
  
  
  RESULTS
  The number of TRAP-positive multinucleated cells in human PBMCs was significantly reduced by miR-146a in a dose-dependent manner. The expression of c-Jun, NF-ATc1, PU.1, and TRAP in PBMCs was significantly down-regulated by miR-146a. Administration of miR-146a prevented joint destruction in mice with CIA, although it did not completely ameliorate inflammation.
  
  
  CONCLUSIONS
  Our findings indicate that expression of miR-146a inhibits osteoclastogenesis and that administration of double-stranded miR-146a prevents joint destruction in arthritic mice. Administration of miR-146a has potential as a novel therapeutic target for bone destruction in RA.
authors.affiliation: Department of Orthopaedic Surgery, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan. tnakasa0@gmail.com
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakasa
authors.forename: Hayatoshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nagata
authors.forename: Takuya
authors.initials: T
authors.lastname: Niimoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ochi
mesh_terms: D000135:Acid Phosphatase / Q000096:biosynthesis; D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D001862:Bone Resorption / Q000628:therapy*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000096:biosynthesis; D010010:Osteoclasts; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D053245:RANK Ligand / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000235:genetics; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators / Q000096:biosynthesis; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000135:Acid Phosphatase; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D016173:Macrophage Colony-Stimulating Factor; D035683:MicroRNAs; D050778:NFATC Transcription Factors; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D012330:RNA, Double-Stranded; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000099232:Proto-Oncogene Protein Spi-1; C542542:MIRN146 microRNA, human; C000605511:Acp5 protein, mouse