IRS2/FOXO1 mitigates osteoarthritis by regulating chondrocyte autophagy and mitochondrial function.

PURPOSE: Osteoarthritis (OA) is a debilitating joint disease with no effective cure. This study investigates the role of Insulin Receptor Substrate 2 (IRS2) in OA and its potential as a therapeutic target.

METHODS

Transcriptomic analysis of OA-related datasets (GSE178557, GSE169077, GSE64394, GSE57218) was conducted to identify differentially expressed genes (DEGs), with KEGG pathway analysis highlighting the PI3K/AKT pathway. In vivo, the destabilization of the medial meniscus (DMM) OA mouse model was used to assess IRS2 expression through histology, qPCR, and Western blot. IRS2 was overexpressed in primary mouse chondrocytes via adenoviral transfection, with proliferation, apoptosis, and autophagy assessed by EdU, Annexin V/PI staining, and autophagy-related protein analysis. Adenovirus expressing Irs2 was injected intra-articularly into DMM mice, and cartilage integrity was assessed using histology and micro-CT.

RESULTS

IRS2 expression was significantly reduced in OA cartilage, correlating with PI3K/AKT pathway inhibition. IRS2 overexpression restored AKT activation, FOXO1 phosphorylation, and mitochondrial autophagy. Intra-articular IRS2 injection improved cartilage matrix integrity, reduced MMP13, and alleviated subchondral bone changes in DMM mice.

CONCLUSION

IRS2 plays a key role in OA pathogenesis and targeting it may provide a promising therapeutic approach for OA.