ATF3 mediates the inhibitory action of TNF-α on osteoblast differentiation through the JNK signaling pathway

Biochem Biophys Res Commun. 2018 May 15;499(3):696-701. doi: 10.1016/j.bbrc.2018.03.214. Epub 2018 Apr 3.


Tumor necrosis factor (TNF)-α, which is a proinflammatory cytokine, inhibits osteoblast differentiation under diverse inflammatory conditions. Activating transcription factor 3 (ATF3), which is a member of the ATF/cAMP response element-binding protein family of transcription factors, has been implicated in the regulation of cell proliferation and differentiation. However, the precise interactions between ATF3 and the TNF-α signaling pathway in the regulation of osteoblast differentiation remain unclear. In this study, we examined the role of ATF3 in the TNF-α-mediated inhibition of osteoblast differentiation and investigated the signaling pathways involved. The treatment of cells with TNF-α downregulated osteogenic markers, but significantly upregulated the expression of Atf3. The inhibition of Atf3 by small interfering RNAs rescued osteogenesis, which was inhibited by TNF-α. Conversely, the enforced expression of Atf3 enhanced the TNF-α-mediated inhibition of osteoblast differentiation, as revealed by the measurement of osteogenic markers and alkaline phosphatase staining. Mechanistically, TNF-α-induced Atf3 expression was significantly suppressed by the inhibition of the c-Jun N-terminal kinase (JNK) pathway. Furthermore, the overexpression of Atf3 did not affect the rescue effect that inhibiting TNF-α expression using a JNK inhibitor had on alkaline phosphatase activity and mineralization. Taken together, these results indicate that ATF3 mediates the inhibitory action of TNF-α on osteoblast differentiation and that the TNF-α-activated JNK pathway is responsible for the induction of Atf3 expression.

Keywords: ATF3; Differentiation; Inflammation; Osteoblast; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism*
  • Animals
  • Cell Differentiation* / drug effects
  • Cell Line
  • Down-Regulation / drug effects
  • Humans
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Osteoblasts / cytology*
  • Osteoblasts / drug effects
  • Osteoblasts / enzymology*
  • Osteogenesis / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Activating Transcription Factor 3
  • Tumor Necrosis Factor-alpha