TRAF family member-associated NF-κB activator (TANK) is a negative regulator of osteoclastogenesis and bone formation

J Biol Chem. 2012 Aug 17;287(34):29114-24. doi: 10.1074/jbc.M112.347799. Epub 2012 Jul 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Bone Density / physiology
  • Cell Differentiation / physiology*
  • Interleukin-11 / genetics
  • Interleukin-11 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Osteogenesis / physiology*
  • RANK Ligand
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitination / physiology


  • Adaptor Proteins, Signal Transducing
  • Interleukin-11
  • Interleukin-6
  • NF-kappa B
  • RANK Ligand
  • RNA, Messenger
  • TNF Receptor-Associated Factor 6
  • Tank protein, mouse
  • Tnfsf11 protein, mouse