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Inhibition of SLC40A1 represses osteoblast formation via inducing iron accumulation and activating the PERK/ATF4/CHOP pathway mediated oxidative stress

  • 0Department of Orthopedics, Medical Affairs Department, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People's Republic of China.
Redox Report : Communications in Free Radical Research +

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November 28, 2024

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November 28, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Solute carrier family 40 member 1 (SLC40A1) inhibition impairs osteoblast formation by increasing iron accumulation and oxidative stress via the PERK/ATF4/CHOP pathway. Restoring SLC40A1 promotes osteoblast differentiation and reduces oxidative stress.

Area Of Science

  • Biochemistry
  • Cell Biology
  • Bone Biology

Background

  • Osteoblast differentiation is crucial for bone health.
  • Iron metabolism and oxidative stress play significant roles in cellular processes.
  • The role of Solute Carrier Family 40 Member 1 (SLC40A1) in osteoblasts requires further elucidation.

Purpose Of The Study

  • To investigate the impact of SLC40A1 on iron accumulation, oxidative stress, and osteoblast differentiation.
  • To explore the underlying molecular mechanisms, including the PERK/ATF4/CHOP pathway.

Main Methods

  • Mouse preosteoblastic MC3T3-E1 cells were utilized.
  • Cells were transfected with SLC40A1 overexpression vectors (oeSLC40A1) or small interfering RNA (siSLC40A1).
  • Cell differentiation was induced, and treatments included ferrostatin-1 and GSK2606414.

Main Results

  • SLC40A1 inhibition (siSLC40A1) increased iron (Fe2+), malondialdehyde (MDA), and reactive oxygen species (ROS), while decreasing the glutathione (GSH)/oxidized glutathione (GSSG) ratio.
  • SLC40A1 overexpression (oeSLC40A1) reversed these effects.
  • Osteoblast differentiation markers (ALP, ARS, OPN, BMP2) were reduced by siSLC40A1 and increased by oeSLC40A1.
  • SLC40A1 negatively regulated the PERK/ATF4/CHOP pathway, which was implicated in the observed iron accumulation and oxidative stress.

Conclusions

  • SLC40A1 inhibition suppresses osteoblast formation.
  • This suppression is mediated by increased iron accumulation and PERK/ATF4/CHOP pathway-driven oxidative stress.
  • Targeting SLC40A1 and related pathways offers potential therapeutic strategies for bone disorders.

Keywords:

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