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

Area of Science:

• Orthopedics and Rheumatology
• Molecular Biology
• Biomedical Research

Background:

• Osteoarthritis (OA) is a prevalent degenerative joint disease with significant unmet therapeutic needs.
• Current OA treatments primarily manage symptoms, lacking disease-modifying capabilities.

Purpose of the Study:

• To investigate the role of Insulin Receptor Substrate 2 (IRS2) in the pathogenesis of osteoarthritis.
• To evaluate IRS2 as a potential therapeutic target for osteoarthritis treatment.

Main Methods:

• Transcriptomic analysis of OA datasets identified dysregulated genes and pathways, including the PI3K/AKT pathway.
• In vivo studies utilized the destabilization of the medial meniscus (DMM) OA mouse model to assess IRS2 expression and function.
• IRS2 was manipulated in primary chondrocytes and intra-articularly injected into DMM mice to evaluate its effects on OA pathology.

Main Results:

• IRS2 expression was significantly downregulated in OA cartilage, correlating with impaired PI3K/AKT signaling.
• IRS2 overexpression in chondrocytes rescued AKT activation, promoted mitochondrial autophagy, and reduced apoptosis.
• Intra-articular IRS2 delivery in DMM mice ameliorated cartilage degradation, decreased matrix metalloproteinase 13 (MMP13) expression, and improved subchondral bone structure.

Conclusions:

• IRS2 plays a critical role in osteoarthritis pathogenesis by regulating key cellular processes.
• Targeting IRS2 represents a promising novel therapeutic strategy for osteoarthritis.