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 journalArticlepeer-review

141 Scopus citations

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 NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB 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 BclXL expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

Original languageEnglish (US)
Pages (from-to)2725-2738
Number of pages14
JournalExperimental Cell Research
Volume314
Issue number15
DOIs
StatePublished - Sep 10 2008

Bibliographical note

Funding Information:
Support for this work was provided by the NIH grant R01 DE14680 and The Mayo Foundation. We thank Dr. Beth Lee for the gift of the GST RANKL expression construct. We also thank Drs. Patricia Collin-Osdoby and Philip Osdoby for their advice on the GST RANKL purification as well as the Mayo Clinic Bone Histomorphometry Core. We are grateful to Dr. Hal Moses for his gift of the TβRII exon 2 floxed mice.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • AKT
  • Apoptosis
  • BclX
  • Mcl-1
  • NFκB
  • Osteoclast
  • Signal transduction
  • SMAD
  • TAK1MEK
  • TGF-β

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