TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival.
To better understand the roles of TGF-beta in bone metabolism, we investigated osteoclast survival in response TGF-beta and found that TGF-beta inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-beta receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-beta treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-beta effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IkappaB, and NFkappaB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFkappaB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFkappaB repressed TGF-beta-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-beta-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX(L) expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-beta-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-beta to support of osteoclast survival.
Gingery
Anne
A
Department of Biochemistry and Molecular Biology, University of Minnesota, Duluth, Minnesota 55812, USA.
Bradley
Elizabeth W
EW
Pederson
Larry
L
Ruan
Ming
M
Horwood
Nikki J
NJ
Oursler
Merry Jo
MJ
D000818:Animals; D001842:Bone and Bones / Q000201:enzymology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D010770:Phosphotransferases; D051057:Proto-Oncogene Proteins c-akt; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C497401:Smad1 protein, mouse; C482127:Map2k1 protein, mouse