TGF-β inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways

Muzaffer Cicek, Anne Vrabel, Catherine Sturchio, Larry Pederson, John R Hawse, Malayannan Subramaniam, Thomas C. Spelsberg, Merry Jo Oursler

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment. As reported previously, TIEG1 -/- mice have decreased cortical bone thickness and vertebral bone volume and have increased spacing between the trabeculae in the femoral head relative to wildtype controls. Here, we have investigated the role of TIEG1 in osteoclasts to further determine their potential role in mediating this phenotype. We have found that TIEG1 -/- osteoclast precursors differentiated more slowly compared to wildtype precursors in vitro and high RANKL doses are able to overcome this defect. We also discovered that TIEG1 -/- precursors exhibit defective RANKL-induced phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. Higher RANKL concentrations reversed defective NFATc1 signaling and restored differentiation. After differentiation, wildtype osteoclasts underwent apoptosis more quickly than TIEG1 -/- osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1 -/- osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1 -/- cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1 -/- precursors and eliminated the differentiation and apoptosis defects. Suppression of TIEG1 with siRNA in wildtype cells reduced differentiation and NFATc1 activation. Together, these data provide evidence that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway activation and reduces osteoclast survival by suppressing AKT and MEK/ERK signaling.

Original languageEnglish (US)
Article numbere17522
JournalPLoS One
Volume6
Issue number3
DOIs
StatePublished - 2011

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osteoclasts
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Osteoclasts
mitogen-activated protein kinase
Genes
Survival
genes
Chemical activation
Defects
Bone
apoptosis
bones
Apoptosis
Phosphorylation
osteoblasts
Osteoblasts
thighs
small interfering RNA
Thigh

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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TGF-β inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. / Cicek, Muzaffer; Vrabel, Anne; Sturchio, Catherine; Pederson, Larry; Hawse, John R; Subramaniam, Malayannan; Spelsberg, Thomas C.; Oursler, Merry Jo.

In: PLoS One, Vol. 6, No. 3, e17522, 2011.

Research output: Contribution to journalArticle

Cicek, Muzaffer ; Vrabel, Anne ; Sturchio, Catherine ; Pederson, Larry ; Hawse, John R ; Subramaniam, Malayannan ; Spelsberg, Thomas C. ; Oursler, Merry Jo. / TGF-β inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. In: PLoS One. 2011 ; Vol. 6, No. 3.
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