IKKβ Activation Is Sufficient for RANK-Independent Osteoclast Differentiation and Osteolysis

Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF-kappa B (RANK). Many downstream effectors of RANK play a positive role in osteoclastogenesis, but their relative importance in osteoclast differentiation is unclear. We report the discovery that activation of a single pathway downstream of RANK is sufficient for osteoclast differentiation. In this regard, introduction of constitutively activated IKK beta (IKK beta(SSEE)) but not wild-type IKK beta into monocytes stimulates differentiation of bona fide osteoclasts in the absence of RANK ligand (RANKL). This phenomenon is independent of upstream signals because IKK beta(SSEE) induced the development of bone-resorbing osteoclasts from RANK and IKK alpha knockout monocytes and in conditions in which NEMO-IKK beta association was inhibited. NF-kappa B p100 and p105, but not RelB, were critical mediators of this effect. Inflammatory autocrine signaling by tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) were dispensable for the spontaneous osteoclastogenesis driven by IKK beta(SSEE). More important, adenoviral gene transfer of IKK beta(SSEE) induced osteoclasts and osteolysis in calvariae and knees of mice. Our data establish the sufficiency of IKK beta activation for osteolysis and suggest that IKK beta hyperactivation may play a role in conditions of pathologic bone destruction refractory to RANK/RANKL proximal therapeutic interventions. (C) 2010 American Society for Bone and Mineral Research.