TY - JOUR
T1 - Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways
AU - Hama, Maasa
AU - Kirino, Yohei
AU - Takeno, Mitsuhiro
AU - Takase, Kaoru
AU - Miyazaki, Takuya
AU - Yoshimi, Ryusuke
AU - Ueda, Atsuhisa
AU - Itoh-Nakadai, Ari
AU - Muto, Akihiko
AU - Igarashi, Kazuhiko
AU - Ishigatsubo, Yoshiaki
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
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U2 - 10.1002/art.33497
DO - 10.1002/art.33497
M3 - Article
C2 - 22127667
AN - SCOPUS:84860491929
SN - 0004-3591
VL - 64
SP - 1518
EP - 1528
JO - Arthritis and Rheumatism
JF - Arthritis and Rheumatism
IS - 5
ER -