Decoding Endoplasmic Reticulum Stress on Chondrocyte Driving Osteoarthritis Development through Integrating...

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.