TGF-β2 drives lipid droplet accumulation in chondrocytes through the TβRI/p-smad3/fabp5 axis.

Chondrocytes preserve cartilage lipid homeostasis by storing neutral lipids in lipid droplets and controlling their turnover through coordinated biochemical signaling. TGF-β2 is elevated in osteoarthritis and regulates key chondrocyte functions, including proliferation, differentiation, and cell death. However, whether and how TGF-β2 regulates chondrocyte lipid metabolism remains unknown. Here, we characterize TGF-β2-regulated lipid droplet accumulation and delineate the underlying mechanism. TGF-β2 drives neutral lipid and lipid droplet accumulation in chondrocytes and cartilage through upregulation of Fabp5. This effect requires TGF-β2 signaling through receptor TβRI, which induces the phosphorylation and nuclear translocation of Smad3, thereby promoting Fabp5 transcription. In this process, TGF-β2 induces enrichment of cellular lipid intermediates involved in lipid droplet accumulation. Collectively, our findings reveal a novel TGF-β2/TβRI/p-Smad3/Fabp5 signaling axis that regulates lipid storage in chondrocytes and suggest potential metabolic targets for maintaining cartilage homeostasis and treating related diseases.