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Decoding Endoplasmic Reticulum Stress on Chondrocyte Driving Osteoarthritis Development through Integrating

Zhao Zhang1, Debin Cheng1, Jingyi Dang1

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International Journal of Medical Sciences
|October 6, 2025
PubMed
Summary
This summary is machine-generated.

Endoplasmic reticulum stress (ERS) drives osteoarthritis (OA) progression by activating unfolded protein responses and apoptosis in chondrocytes. Key regulators IGFBP3 and S100A4 offer diagnostic and therapeutic potential for OA.

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Area of Science:

  • Molecular Biology
  • Genomics
  • Biochemistry

Background:

  • Endoplasmic reticulum stress (ERS) is implicated in various diseases.
  • Osteoarthritis (OA) involves chondrocyte damage, but ERS's role in OA chondrocytes is unclear.

Purpose of the Study:

  • Investigate the role of ERS in OA pathogenesis.
  • Identify key ERS regulators for OA diagnosis and treatment.

Main Methods:

  • Integrated single-cell and bulk RNA sequencing (scRNA-seq, RNA-seq) to analyze ERS in OA chondrocytes.
  • Applied Weighted Gene Co-expression Network Analysis (WGCNA) and clustering to identify ERS patterns.
  • Screened ERS regulators using LASSO, Random Forest, and protein-protein interaction (PPI) analysis; validated findings in vitro.

Main Results:

  • ERS is robustly associated with OA progression, with heightened unfolded protein responses, TNFα signaling, and apoptosis in high-ERS subpopulations.
  • Identified two key ERS regulators, IGFBP3 and S100A4, and developed a predictive nomogram for OA.
  • In vitro suppression of IGFBP3 maintained chondrocyte homeostasis and reduced apoptosis by inhibiting the PERK/ATF4/CHOP pathway.

Conclusions:

  • ERS significantly contributes to OA pathogenesis and progression.
  • IGFBP3 and S100A4 are crucial ERS regulators with potential for OA diagnosis and therapy.
  • Targeting ERS pathways offers a promising therapeutic strategy for OA.