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<p>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.</p><p></p>

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Dapagliflozin regulates chondrocyte homeostasis and protects against osteoarthritis via targets AMPKα and SGLT2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Kaiwen Liu,
  • Zedi Li,
  • Cheng Wang,
  • Houyi Sun,
  • Jie Zhao,
  • Meng Si

摘要

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.