Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways.
Arthritis Rheum
; 64(5): 1518-28, 2012 May.
Article
en En
| MEDLINE
| ID: mdl-22127667
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Osteoclastos
/
Resorción Ósea
/
Hemo-Oxigenasa 1
/
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico
/
Proteínas de la Membrana
Límite:
Animals
Idioma:
En
Revista:
Arthritis Rheum
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón