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The intracellular NADH level regulates atrophic nonunion pathogenesis through the CtBP2-p300-Runx2 transcriptional

Wentao Zhang1,2, Ning Duan2, Qian Zhang3

  • 1Department of Orthopedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710005, Shaanxi, China.

International Journal of Biological Sciences
|December 27, 2018
PubMed

Insights

Carboxyl-terminal binding protein 2 (CtBP2) is overexpressed in atrophic nonunion, hindering bone healing. Lower NADH levels disrupt CtBP2 binding to p300-Runx2, blocking bone-related gene expression.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Orthopedics

Background:

  • Atrophic nonunion is a complex fracture healing failure with unclear molecular mechanisms.
  • Carboxyl-terminal binding proteins (CtBPs) are NADH-sensitive transcriptional corepressors implicated in various diseases.

Purpose of the Study:

  • To investigate the role of CtBP2 in the molecular pathology of atrophic nonunion.
  • To elucidate the mechanism by which CtBP2 influences bone-related gene expression in nonunion.

Main Methods:

  • Mass spectrometry to identify protein complexes involving CtBP2.
  • Analysis of CtBP2 and NADH levels in atrophic nonunion tissues.
  • Investigating the effect of NADH levels on gene expression in vitro.

Main Results:

  • CtBP2, not CtBP1, is significantly overexpressed in atrophic nonunion tissues.
  • CtBP2 forms a complex with p300 and Runx2.
  • Reduced NADH levels in nonunion disrupt CtBP2 dimerization, impairing p300-Runx2 access to bone-related gene promoters (e.g., OSC, ALPL, COL1A1).
  • Restoring NADH levels with CoCl2 reversed the downregulation of these genes.

Conclusions:

  • CtBP2 acts as a NADH-dependent repressor of the p300-Runx2 transcriptional complex.
  • NADH levels critically regulate CtBP2 binding to p300-Runx2, thereby controlling the expression of genes essential for bone formation and development.
  • This mechanism provides new insights into atrophic nonunion pathogenesis and potential therapeutic targets.
Keywords:
CtBP2NADH/NAD ratioRunx2atrophic nonunionp300

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