NF-kappaB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism.

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave.,Rochester, NY 14642, USA.
The Journal of clinical investigation (Impact Factor: 15.39). 09/2009; 119(10):3024-34. DOI: 10.1172/JCI38716
Source: PubMed

ABSTRACT TNF and RANKL mediate bone destruction in common bone diseases, including osteoarthritis and RA. They activate NF-kappaB canonical signaling directly in osteoclast precursors (OCPs) to induce osteoclast formation in vitro. However, unlike RANKL, TNF does not activate the alternative NF-kappaB pathway efficiently to process the IkappaB protein NF-kappaB p100 to NF-kappaB p52, nor does it appear to induce osteoclast formation in vivo in the absence of RANKL. Here, we show that TNF limits RANKL- and TNF-induced osteoclast formation in vitro and in vivo by increasing NF-kappaB p100 protein accumulation in OCPs. In contrast, TNF induced robust osteoclast formation in vivo in mice lacking RANKL or RANK when the mice also lacked NF-kappaB p100, and TNF-Tg mice lacking NF-kappaB p100 had more severe joint erosion and inflammation than did TNF-Tg littermates. TNF, but not RANKL, increased OCP expression of TNF receptor-associated factor 3 (TRAF3), an adapter protein that regulates NF-kappaB p100 levels in B cells. TRAF3 siRNA prevented TNF-induced NF-kappaB p100 accumulation and inhibition of osteoclastogenesis. These findings suggest that upregulation of TRAF3 or NF-kappaB p100 expression or inhibition of NF-kappaB p100 degradation in OCPs could limit bone destruction and inflammation-induced bone loss in common bone diseases.

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