ATF4 promotes β-catenin expression and osteoblastic differentiation of bone marrow mesenchymal stem cells

Shibing Yu, Ke Zhu, Yumei Lai, Zhongfang Zhao, Jie Fan, Hee Jeong Im, Di Chen, Guozhi Xiao

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Bone marrow mesenchymal stem cells (MSCs) can differentiate into multiple cell types including osteoblasts. How this differentiation process is controlled, however, is not completely understood. Here we show that activating transcription factor 4 (ATF4) plays a critical role in promoting bone marrow MSC differentiation towards the osteoblast lineage. Ablation of the Atf4 gene blocked the formation of osteoprogenitors and inhibited osteoblast differentiation without affecting the expansion and formation of MSCs in bone marrow cultures. Loss of ATF4 dramatically reduced the level of β-catenin protein in MSCs in vitro and in osteoblasts/osteoprogenitors located on trabecular and calvarial surfaces. Loss of ATF4 did not decrease the expression of major canonical Wnt/β-catenin signaling components such as Wnt3a, Wnt7b, Wnt10b, Lrp5, and Lrp6 in MSCs. Furthermore, shRNA knockdown of ATF4 expression decreased the level of β-catenin protein in MC-4 preosteoblasts. In contrast, overexpression of ATF4 increased β-catenin protein levels in MC-4 cells. Finally, ATF4 and β-catenin formed a protein-protein complex in COS-7 cells coexpressing both factors or in MC-4 preosteoblastic cells. This study establishes a new role of ATF4 in controlling the β-catenin protein levels and MSC differentiation towards the osteoblast lineage.

Original languageEnglish (US)
Pages (from-to)256-266
Number of pages11
JournalInternational Journal of Biological Sciences
Volume9
Issue number3
DOIs
StatePublished - Feb 27 2013
Externally publishedYes

Keywords

  • ATF4
  • Bone
  • MSC
  • Osteoblast
  • β-catenin

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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