Abstract Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation and a complex pathogenesis. Degenerated chondrocytes exhibit an imbalance between catabolism and anabolism, leading to cartilage matrix loss. Currently, there are no effective clinical therapies to halt or reverse this degeneration. This study investigated the therapeutic potential of Dapagliflozin (DAPA) for OA. We demonstrated that DAPA exerts protective effects on cartilage explants from patients with OA as well as in surgically induced OA models in mice. In vitro studies revealed that DAPA ameliorates OA by restoring chondrocyte metabolic homeostasis. Transcriptome sequencing showed that DAPA activated the AMP-activated protein kinase (AMPK) signaling pathway while suppressing MAPK signaling. Mechanistically, AMPKα was identified as a novel target of DAPA. DAPA alleviated excessive catabolism by targeting both AMPKα and SGLT2, while promoting anabolic processes through AMPKα activation. Furthermore, DAPA rescued impaired autophagy caused by SGLT2 upregulation in degenerated chondrocytes. Our findings demonstrated that DAPA regulates cartilage metabolism by concurrently modulating AMPKα and SGLT2, underscoring the therapeutic promise of combined AMPK activation and SGLT2 inhibition in OA treatment.
Liu et al. (Thu,) studied this question.