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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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Transforming growth factor β suppresses osteoblast differentiation via the vimentin activating transcription factor 4

Na Lian1, Tonghui Lin, Wenguang Liu

  • 1Vanderbilt Center for Bone Biology, Nashville, Tennessee 37232, USA.

The Journal of Biological Chemistry
|September 7, 2012
PubMed

Insights

Transforming growth factor beta (TGFβ) suppresses osteoblast differentiation by increasing vimentin, which inhibits the transcription factor ATF4. ATF4 is essential for TGFβ

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Bone Biology

Background:

  • Activating Transcription Factor 4 (ATF4) is an osteoblast-specific transcription factor.
  • Vimentin, an intermediate filament protein, negatively regulates ATF4 activity and osteoblast differentiation.
  • Transforming growth factor beta (TGFβ) signaling plays a role in bone metabolism.

Purpose of the Study:

  • To investigate the mechanism by which TGFβ regulates ATF4-dependent osteocalcin (Ocn) transcription and osteoblast differentiation.
  • To determine the role of vimentin in mediating TGFβ's effects on osteoblasts.
  • To elucidate the signaling pathways involved in TGFβ-induced vimentin expression.

Main Methods:

  • ব্যবহার of Atf4 knockout (Atf4(-/-)) and wild-type (WT) osteoblasts.
  • TGFβ treatment and assessment of alkaline phosphatase activity, Ocn transcription, and mineralization.
  • Vimentin knockdown experiments.
  • In vivo studies using WT and Atf4(-/-) mice treated with a TGFβ-neutralizing antibody.
  • Inhibition of PI3K/Akt/mTOR and Smad signaling pathways.

Main Results:

  • TGFβ inhibits ATF4-dependent Ocn transcription and osteoblast differentiation by up-regulating vimentin expression.
  • Osteoblasts lacking ATF4 are less sensitive to TGFβ-induced inhibition of differentiation markers.
  • The anabolic effect of TGFβ neutralization on bone is diminished in Atf4(-/-) mice.
  • TGFβ enhances vimentin expression post-transcriptionally, not by directly regulating ATF4.
  • Vimentin knockdown abolishes TGFβ-mediated suppression of Ocn transcription.
  • Inhibition of PI3K/Akt/mTOR signaling blocks TGFβ-induced vimentin synthesis and Ocn transcription suppression.

Conclusions:

  • ATF4 is crucial for the suppressive effects of TGFβ on osteoblast differentiation and Ocn transcription.
  • TGFβ exerts its inhibitory effects indirectly through the induction of vimentin via the PI3K-Akt-mTOR pathway.
  • Vimentin acts as a key mediator linking TGFβ signaling to the suppression of ATF4 activity in osteoblasts.

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