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Phosphoglycerate kinase 1 silencing by a novel microRNA microRNA-4523 protects human osteoblasts from dexamethasone

Jin-Qian Liang1, Zhen-Tao Zhou2, Lin Bo3

  • 1Department of Orthopaedics, Peking Union Medical College Hospital, Beijing, China.

Cell Death & Disease
|October 20, 2021
PubMed

Insights

MicroRNA-4523 (miR-4523) protects human osteoblasts from dexamethasone (DEX) by targeting phosphoglycerate kinase 1 (PGK1). This activates the Nrf2 pathway, reducing oxidative stress and cell death, offering a novel therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Dexamethasone (DEX) induces oxidative injury and apoptosis in human osteoblasts.
  • Nuclear-factor-E2-related factor 2 (Nrf2) activation can protect against DEX-induced damage.
  • Phosphoglycerate kinase 1 (PGK1) depletion activates Nrf2 signaling.

Purpose of the Study:

  • To identify and characterize a novel microRNA targeting PGK1.
  • To investigate the role of this microRNA in activating the Nrf2 cascade.
  • To determine if this microRNA can protect osteoblasts from DEX-induced injury.

Main Methods:

  • RNA fluorescent in situ hybridization, RNA pull-down, and Argonaute-2 RNA immunoprecipitation to confirm miR-4523 and PGK1 interaction.
  • Lentiviral constructs for miR-4523 overexpression and PGK1 knockout (CRISPR/Cas9).
  • Assessment of Nrf2 signaling activation, gene expression (NQO1, GCLC, HO1), reactive oxygen species production, and cell apoptosis.

Main Results:

  • MicroRNA-4523 (miR-4523) directly binds to PGK1 mRNA, downregulating PGK1 expression in osteoblasts.
  • miR-4523 overexpression activates the Nrf2 cascade by promoting Keap1-Nrf2 disassociation and Nrf2 nuclear translocation.
  • miR-4523 significantly attenuates DEX-induced oxidative stress, injury, and apoptosis, an effect dependent on Nrf2 and PGK1.
  • miR-4523 is downregulated in human osteonecrosis tissues from DEX-treated patients.

Conclusions:

  • PGK1 silencing by miR-4523 protects human osteoblasts against DEX-induced damage via Nrf2 pathway activation.
  • miR-4523 represents a potential therapeutic target for preventing DEX-induced osteotoxicity.

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