Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes

Jishang Huang1, Zhixi Chen2, Zhenyu Wu3

  • 1Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.

Insights

Geniposide (GEN) stimulates autophagy and protects osteoarthritis cartilage by activating the GLP-1R/AMPK/mTOR pathway. This natural compound enhances chondrocyte homeostasis, offering a potential therapeutic strategy for osteoarthritis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Osteoarthritis (OA) is a degenerative joint disease where chondrocyte homeostasis is disrupted.
  • Autophagy plays a crucial role in maintaining chondrocyte health and protecting against OA.
  • Geniposide (GEN), from Eucommia ulmoides Oliv, activates GLP-1R and stimulates autophagy.

Purpose of the Study:

  • To investigate if GEN protects OA chondrocytes by activating the GLP-1R/AMPK/mTOR signaling pathway.
  • To elucidate the role of GEN in mediating autophagic responses in OA.

Main Methods:

  • Utilized MIA-induced rat OA models to observe autophagy levels.
  • Treated IL-1β-induced C28/I2 cells with GEN to assess effects on autophagy and signaling pathways.
  • Employed AMPK inhibitors and mTOR activators to study GEN's mechanism.
  • Used a GLP-1R inhibitor (Exendin 9-39) to confirm pathway involvement.

Main Results:

  • MIA-induced OA models showed reduced autophagy (increased p62, decreased Beclin-1 and LC3-II/I).
  • GEN upregulated GLP-1R expression, stimulated autophagy, and protected OA cartilage.
  • GEN enhanced AMPK phosphorylation and reduced mTOR expression in chondrocytes.
  • Inhibiting AMPK or activating mTOR reversed GEN's autophagy-promoting effects.
  • Exendin 9-39 blocked GEN's chondroprotective effects by suppressing the AMPK/mTOR pathway.

Conclusions:

  • Geniposide demonstrates chondroprotective effects against osteoarthritis development.
  • GEN stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling pathway in OA chondrocytes.
  • GEN represents a potential therapeutic agent for osteoarthritis by modulating autophagy and key signaling pathways.

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