Osteoclast Differentiation Requires TAK1 and MKK6 for NFATc1 Induction and NF-kappaB Transactivation by RANKL

Cell Death Differ. 2006 Nov;13(11):1879-91. doi: 10.1038/sj.cdd.4401882. Epub 2006 Feb 24.


Osteoclast (Oc) differentiation is fundamentally controlled by receptor activator of nuclear factor kappaB ligand (RANKL). RANKL signalling targets include mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-kappaB), and nuclear factor of activated T cells (NFAT)c1. In this study, we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced p38 activation. Retroviral transduction of dominant-negative (DN) forms of TAK1 and MKK6, but not that of MKK3, reduced Oc differentiation. Transduction of TAK1-DN and MKK6-DN and treatment with the p38 inhibitor SB203580 attenuated NFATc1 induction by RANKL. TAK1-DN, MKK6-DN, and SB203580, but not MKK3-DN, also suppressed RANKL stimulation of NF-kappaB transcription activity in a manner dependent on p65 phosphorylation on Ser-536. These results indicate that TAK1 and MKK6 constitute the p38 signalling pathway to participate to Oc differentiation by RANKL through p65 phosphorylation and NFATc1 induction, and that MKK6 and MKK3 have differential roles in osteoclastogenesis from bone marrow precursors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • MAP Kinase Kinase 3 / antagonists & inhibitors
  • MAP Kinase Kinase 6 / antagonists & inhibitors
  • MAP Kinase Kinase 6 / metabolism*
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / cytology*
  • Osteogenesis / drug effects
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • RANK Ligand / pharmacology*
  • Signal Transduction / drug effects
  • Stem Cells / drug effects
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / drug effects*
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • NF-kappa B
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • Phosphoserine
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • Map2k3 protein, mouse
  • Map2k6 protein, mouse