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p300 arrests intervertebral disc degeneration by regulating the FOXO3/Sirt1/Wnt/β-catenin axis

Yingjie Hao1, Zhinan Ren1, Lei Yu1

  • 1Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Aging Cell
|July 30, 2022
PubMed

Insights

The transcription factor p300 suppresses intervertebral disc degeneration (IDD) by upregulating FOXO3, which inactivates the Wnt/β-catenin pathway. This finding highlights p300 as a potential therapeutic target for IDD.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Regenerative Medicine

Background:

  • The transcription factor p300 is implicated in age-related diseases, including intervertebral disc degeneration (IDD).
  • Understanding the role of p300 in IDD pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role and underlying mechanisms of p300 in IDD.
  • To explore the relationship between p300, FOXO3, Sirt1, and the Wnt/β-catenin pathway in IDD.

Main Methods:

  • Analysis of p300, FOXO3, and Sirt1 expression in human IDD tissues and nucleus pulposus cells (NPCs).
  • In vitro experiments using NPCs with manipulated p300 and FOXO3 levels, and Wnt/β-catenin pathway modulators.
  • Establishment and analysis of a rat IDD model to validate in vivo findings.

Main Results:

  • p300 expression was decreased in IDD tissues and NPCs.
  • Overexpression of p300 enhanced NPC proliferation and autophagy, inhibited apoptosis, and upregulated FOXO3.
  • p300 increased FOXO3 expression by targeting the Sirt1 promoter, leading to Wnt/β-catenin pathway inactivation.
  • In vivo, p300 mitigated IDD progression by inhibiting the Wnt/β-catenin pathway via the FOXO3/Sirt1 axis.

Conclusions:

  • p300 acts as a suppressor of IDD through a FOXO3-dependent mechanism.
  • The p300/FOXO3/Sirt1/Wnt/β-catenin axis represents a potential therapeutic strategy for IDD.
Keywords:
AutophagyFOXO3Intervertebral disc degenerationNucleus pulposus cellsSirt1Wnt/β-catenin pathwayp300

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