TY - JOUR
T1 - Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL
AU - Huang, H.
AU - Ryu, J.
AU - Ha, J.
AU - Chang, E. J.
AU - Kim, H. J.
AU - Kim, H. M.
AU - Kitamura, T.
AU - Lee, Z. H.
AU - Kim, H. H.
N1 - Funding Information:
We thank Drs Tohru Ishitani and Roger J Davis for kindly providing plasmids. We are also grateful to Dr Paul McCray for providing an adenoviral NF-kB reporter system through the Gene Transfer Vector Core at the University of Iowa. This work was supported by the 21C Frontier Functional Proteomics Project Grant (FPR05C2-280) and the Molecular and Cellular BioDiscovery Research Program (M1-0311-00-0024) from the Ministry of Science and Technology, Korea.
PY - 2006/11
Y1 - 2006/11
N2 - 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-κB), 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-κB 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.
AB - 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-κB), 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-κB 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.
UR - https://www.scopus.com/pages/publications/33749609382
UR - https://www.scopus.com/pages/publications/33749609382#tab=citedBy
U2 - 10.1038/sj.cdd.4401882
DO - 10.1038/sj.cdd.4401882
M3 - Article
C2 - 16498455
AN - SCOPUS:33749609382
SN - 1350-9047
VL - 13
SP - 1879
EP - 1891
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 11
ER -