title: TRAF family member-associated NF-κB activator (TANK) is a negative regulator of osteoclastogenesis and bone formation.
abstract: The differentiation of bone-resorbing osteoclasts is induced by RANKL signaling, and leads to the activation of NF-κB via TRAF6 activation. TRAF family member-associated NF-κB activator (TANK) acts as a negative regulator of Toll-like receptors (TLRs) and B-cell receptor (BCR) signaling by inhibiting TRAF6 activation. Tank(-/-) mice spontaneously develop autoimmune glomerular nephritis in an IL-6-dependent manner. Despite its importance in the TCRs and BCR-activated TRAF6 inhibition, the involvement of TANK in RANKL signaling is poorly understood. Here, we report that TANK is a negative regulator of osteoclast differentiation. The expression levels of TANK mRNA and protein were up-regulated during RANKL-induced osteoclastogenesis, and overexpression of TANK in vitro led to a decrease in osteoclast formation. The in vitro osteoclastogenesis of Tank(-/-) cells was significantly increased, accompanied by increased ubiquitination of TRAF6 and enhanced canonical NF-κB activation in response to RANKL stimulation. Tank(-/-) mice showed severe trabecular bone loss, but increased cortical bone mineral density, because of enhanced bone erosion and formation. TANK mRNA expression was induced during osteoblast differentiation and Tank(-/-) osteoblasts exhibited enhaced NF-κB activation, IL-11 expression, and bone nodule formation than wild-type control cells. Finally, wild-type mice transplanted with bone marrow cells from Tank(-/-) mice showed trabecular bone loss analogous to that in Tank(-/-) mice. These findings demonstrate that TANK is critical for osteoclastogenesis by regulating NF-κB, and is also important for proper bone remodeling.
authors: Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Kenta
authors: K
authors: Maruyama
authors: Tatsukata
authors: T
authors: Kawagoe
authors: Takeshi
authors: T
authors: Kondo
authors: Shizuo
authors: S
authors: Akira
authors: Osamu
authors: O
authors: Takeuchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015519:Bone Density / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017370:Interleukin-11; D015850:Interleukin-6; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D048029:TNF Receptor-Associated Factor 6; C100814:Tank protein, mouse; C505689:Tnfsf11 protein, mouse