title: Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways.
abstract: OBJECTIVE
  Reducing inflammation and osteoclastogenesis by heme oxygenase 1 (HO-1) induction could be beneficial in the treatment of rheumatoid arthritis (RA). However, the function of HO-1 in bone metabolism remains unclear. This study was undertaken to clarify the effects of HO-1 and its repressor Bach1 in osteoclastogenesis.
  
  
  METHODS
  In vitro osteoclastogenesis was compared in Bach1-deficient and wild-type mice. Osteoclasts (OCs) were generated from bone marrow-derived macrophages by stimulation with macrophage colony-stimulating factor and RANKL. Osteoclastogenesis was assessed by tartrate-resistant acid phosphatase staining and expression of OC-related genes. Intracellular signal pathways in OC precursors were also assessed. HO-1 short hairpin RNA (shRNA) was transduced into Bach1(-/-)  mouse bone marrow-derived macrophages to examine the role of HO-1 in osteoclastogenesis. In vivo inflammatory bone loss was evaluated by local injection of tumor necrosis factor α (TNFα) into calvaria.
  
  
  RESULTS
  Transcription of HO-1 was down-regulated by stimulation with RANKL in the early stage of OC differentiation. Bach1(-/-)  mouse bone marrow-derived macrophages were partially resistant to the RANKL-dependent HO-1 reduction and showed impaired osteoclastogenesis, which was associated with reduced expression of RANK and components of the downstream TNF receptor-associated factor 6/c-Fos/NF-ATc1 pathway as well as reduced expression of Blimp1. Treatment with HO-1 shRNA increased the number of OCs and expression of OC-related genes except for the Blimp1 gene during in vitro osteoclastogenesis from Bach1(-/-)  mouse bone marrow-derived macrophages. TNFα-induced bone destruction was reduced in Bach1(-/-)  mice in vivo.
  
  
  CONCLUSIONS
  The present findings demonstrate that Bach1 regulates osteoclastogenesis under inflammatory conditions, via both HO-1-dependent and HO-1-independent mechanisms. Bach1 may be worthy of consideration as a target for treatment of inflammatory bone loss in diseases including RA.
authors: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Maasa
authors: M
authors: Hama
authors: Yohei
authors: Y
authors: Kirino
authors: Mitsuhiro
authors: M
authors: Takeno
authors: Kaoru
authors: K
authors: Takase
authors: Takuya
authors: T
authors: Miyazaki
authors: Ryusuke
authors: R
authors: Yoshimi
authors: Atsuhisa
authors: A
authors: Ueda
authors: Ari
authors: A
authors: Itoh-Nakadai
authors: Akihiko
authors: A
authors: Muto
authors: Kazuhiko
authors: K
authors: Igarashi
authors: Yoshiaki
authors: Y
authors: Ishigatsubo
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology*; D053245:RANK Ligand / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012886:Skull / Q000187:drug effects / Q000473:pathology; D000071681:Tartrate-Resistant Acid Phosphatase; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D015415:Biomarkers; D007527:Isoenzymes; D008565:Membrane Proteins; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase