Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways

Maasa Hama, Yohei Kirino, Mitsuhiro Takeno, Kaoru Takase, Takuya Miyazaki, Ryusuke Yoshimi, Atsuhisa Ueda, Ari Itoh-Nakadai, Akihiko Muto, Kazuhiko Igarashi, Yoshiaki Ishigatsubo

Research output: Contribution to journalArticle

18 Citations (Scopus)

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. Conclusion 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.

Original languageEnglish
Pages (from-to)1518-1528
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number5
DOIs
Publication statusPublished - 2012 May

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways'. Together they form a unique fingerprint.

  • Cite this

    Hama, M., Kirino, Y., Takeno, M., Takase, K., Miyazaki, T., Yoshimi, R., Ueda, A., Itoh-Nakadai, A., Muto, A., Igarashi, K., & Ishigatsubo, Y. (2012). Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways. Arthritis and Rheumatism, 64(5), 1518-1528. https://doi.org/10.1002/art.33497