TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Anne Gingery, Elizabeth W Bradley, Larry Pederson, Ming Ruan, Nikki J. Horwood, Merry Jo Oursler

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-β 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-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-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-β-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

Original languageEnglish
Pages (from-to)2725-2738
Number of pages14
JournalExperimental Cell Research
Volume314
Issue number15
Early online date13 Jun 2008
DOIs
Publication statusPublished - 10 Sep 2008

Keywords

  • Animals
  • Bone and Bones/enzymology
  • Cell Line
  • Cell Survival/drug effects
  • Cells, Cultured
  • Enzyme Activation/drug effects
  • Gene Expression Regulation, Enzymologic/drug effects
  • MAP Kinase Kinase 1/metabolism
  • MAP Kinase Kinase Kinases/metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B/metabolism
  • Osteoclasts/drug effects
  • Phosphorylation
  • Phosphotransferases/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/drug effects
  • Smad1 Protein/metabolism
  • Transcriptional Activation/drug effects
  • Transforming Growth Factor beta/metabolism

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