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Published on: October 28, 2019
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.
Abstract:
Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration. Autophagy is associated with chondrocyte homeostasis and exhibits a role in protecting against OA pathogenesis. Geniposide (GEN), an iridoid glycoside extracted from Eucommia ulmoides Oliv, acts as an activator of GLP-1R, which can stimulate autophagy. The AMPK/mTOR signaling pathway participates in the mediation of autophagy, and GLP-1R may act as an upstream factor of AMPK. However, whether GEN mediates the autophagic responses by activating the GLP-1R/AMPK/mTOR signaling pathway in OA chondrocytes is still unclear. In the current study, attenuated autophagy in MIA-induced rat OA models was observed, as shown by up-regulated expression of p62 and down-regulated expression of Beclin-1 and LC3-II/I. GEN stimulated autophagy and protected OA cartilage by up-regulating GLP-1R expression. In addition, GEN could enhance AMPK phosphorylation and down-regulate mTOR expression in IL-1β-treated C28/I2 cells. Inhibition of AMPK or activation of mTOR could reverse the stimulatory effects of GEN on autophagy. Furthermore, a GLP-1R inhibitor Exendin 9-39 could eliminate the chondroprotective effects of GEN by suppressing the AMPK/mTOR signaling pathway. Conclusively, Geniposide exhibits protective effects against osteoarthritis development by stimulating autophagy via activating the GLP-1R/AMPK/mTOR signaling pathway.
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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