PPARβ/δ priming enhances mesenchymal stromal cell anti-apoptotic properties on chondrocytes via ANGPTL4 and improves their therapeutic effects in osteoarthritis.

Abstract

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, chondrocyte apoptosis, and inflammation. Mesenchymal stromal cells (MSCs) offer therapeutic potential, but their efficacy is hindered by oxidative stress and functional heterogeneity. We investigated whether PPARβ/δ priming enhances MSC therapeutic properties and explored the underlying mechanisms.

Methods: MSCs were primed with the PPARβ/δ agonist GW501516. In a collagenase-induced OA mouse model, we assessed cartilage integrity by confocal laser scanning microscopy and histological grading. In vitro, we evaluated the effects of primed MSCs on oxidative stress resistance, chondrocyte apoptosis, and immunomodulation using DNA fragmentation, co-culture assays, and RNA sequencing.

Results: PPARβ/δ priming significantly enhanced MSC resistance to oxidative stress, preserving their survival under H2O2-induced conditions. In co-culture experiments, primed MSCs exhibited a superior chondroprotective effect, reducing apoptosis in stressed chondrocytes. In vivo, primed MSCs improved cartilage volume, thickness, and integrity, lowering OA severity scores. RNA sequencing identified ANGPTL4 as a key mediator of these effects, as its silencing abolished MSC-mediated chondroprotection.

Conclusion: PPARβ/δ priming enhances the therapeutic potential of MSCs by increasing their resistance to oxidative stress and anti-apoptotic effects on chondrocytes, mediated by ANGPTL4. These findings suggest a promising strategy for optimizing MSC-based therapies for OA.