Ubiquitin-like domain of IKKß regulates osteoclastogenesis and osteolysis.
Calcif Tissue Int
; 93(1): 78-85, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23686246
ABSTRACT
The transcription factor NF-κB family is central for osteoclastogenesis and inflammatory osteolysis. Activation of NF-κB dimers is regulated by a kinase complex predominantly containing IKKα (IKK1), IKKß (IKK2), and a regulatory subunit, IKKγ/NEMO. IKKα and IKKß catalyze the cytoplasmic liberation and nuclear translocation of various NF-κB subunits. The requirement of IKKα and IKKß for normal bone homeostasis has been established. Congruently, mice devoid of IKKα or IKKß exhibit in vitro and in vivo defects in osteoclastogenesis, and IKKß-null mice are refractory to inflammatory arthritis and osteolysis. To better understand the molecular mechanism underlying IKKß function in bone homeostasis and bone pathologies, we conducted structure-function analysis to determine IKKß functional domains in osteoclasts. IKKß encompasses several domains, of which the ubiquitination-like domain (ULD) has been shown essential for IKKß activation. In this study, we examined the role of ULD in IKKß-mediated NF-κB activation in osteoclast precursors and its contribution to osteoclastogenesis and osteolysis. We generated and virally introduced IKKß in which the ULD domain has been deleted (IKKß∆ULD) into osteoclast progenitors. The results show that deletion of ULD diminishes IKKß activity and that IKKß∆ULD strongly inhibits osteoclastogenesis. In addition, unlike wild type (WT)-IKKß, IKKß∆ULD fail to restore RANKL-induced osteoclastogenesis by IKKß-null precursors. Finally, we provide evidence that IKKß∆ULD blocks inflammatory osteolysis in a model of murine calvarial osteolysis. Thus, we identified the ULD as crucial for IKKß activity and osteoclastogenesis and found that ULD-deficient IKKß is a potent inhibitor of osteoclastogenesis and osteolysis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteoclastos
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Osteólise
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Quinase I-kappa B
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Calcif Tissue Int
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos