Ubiquitin-Like Domain of IKKβ Regulates Osteoclastogenesis and Osteolysis

The transcription factor NF-kappa B family is central for osteoclastogenesis and inflammatory osteolysis. Activation of NF-kappa B dimers is regulated by a kinase complex predominantly containing IKK alpha (IKK1), IKK beta (IKK2), and a regulatory subunit, IKK gamma/NEMO. IKK alpha and IKK beta catalyze the cytoplasmic liberation and nuclear translocation of various NF-kappa B subunits. The requirement of IKK alpha and IKK beta for normal bone homeostasis has been established. Congruently, mice devoid of IKK alpha or IKK beta exhibit in vitro and in vivo defects in osteoclastogenesis, and IKK beta-null mice are refractory to inflammatory arthritis and osteolysis. To better understand the molecular mechanism underlying IKK beta function in bone homeostasis and bone pathologies, we conducted structure-function analysis to determine IKK beta functional domains in osteoclasts. IKK beta encompasses several domains, of which the ubiquitination-like domain (ULD) has been shown essential for IKK beta activation. In this study, we examined the role of ULD in IKK beta-mediated NF-kappa B activation in osteoclast precursors and its contribution to osteoclastogenesis and osteolysis. We generated and virally introduced IKK beta in which the ULD domain has been deleted (IKK beta a dagger ULD) into osteoclast progenitors. The results show that deletion of ULD diminishes IKK beta activity and that IKK beta a dagger ULD strongly inhibits osteoclastogenesis. In addition, unlike wild type (WT)-IKK beta, IKK beta a dagger ULD fail to restore RANKL-induced osteoclastogenesis by IKK beta-null precursors. Finally, we provide evidence that IKK beta a dagger ULD blocks inflammatory osteolysis in a model of murine calvarial osteolysis. Thus, we identified the ULD as crucial for IKK beta activity and osteoclastogenesis and found that ULD-deficient IKK beta is a potent inhibitor of osteoclastogenesis and osteolysis.