Celastrol Promotes Chondrocyte Autophagy by Regulating mTOR Expression—A Step Toward Better Osteoarthritis Treatments
Osteoarthritis (OA) affects over 300 million people worldwide, making it one of the most common causes of chronic pain and disability. Yet, effective treatments that slow or stop its progression remain frustratingly limited. Autophagy—your cells’ natural “clean-up” process—plays a key role in protecting cartilage from damage, but it’s often suppressed in OA. Now, a study from Chinese researchers offers hope by uncovering how a natural compound—celastrol—might protect the cartilage cells (chondrocytes) damaged by OA.
What Is Celastrol?
Celastrol is a triterpenoid quinine methide extracted from the roots of Tripterygium wilfordii Hook F., a plant used in traditional Chinese medicine. Lab studies and early clinical work have shown it can slow arthritis progression, but exactly how it works in OA has been unclear—until now.
The Study: Focus on mTOR and Autophagy
Researchers from Harbin Medical University and related institutions set out to test a key hypothesis: Could celastrol protect OA chondrocytes by targeting mTOR (mammalian target of rapamycin), a protein that acts as a “brake” on autophagy? If celastrol inhibited mTOR, it might turn autophagy back on and shield chondrocytes from OA-related harm.
How the Study Worked
First, the team used a Cell Counting Kit-8 (CCK-8) assay to find the safe, effective dose of celastrol for chondrocyte cultures: 200 nmol/L for 24 hours. This dose didn’t harm cells but was strong enough to trigger biological effects.
Next, they measured protein levels using Western blotting—a technique to track cellular “signals.” They focused on three key markers:
- mTOR: The hypothesized target of celastrol.
- P62: A protein that builds up when autophagy is low (lower P62 = more autophagy).
- LC3: A protein that changes from LC3-I to LC3-II when autophagosomes (the cell’s “trash bags”) form (more LC3-II = more autophagy).
Key Results: Celastrol Boosts Autophagy by Inhibiting mTOR
The data told a clear story:
- Celastrol reduced mTOR levels in OA chondrocytes.
- It lowered P62 and increased LC3-II—signs that autophagy was ramping up.
In short: Celastrol was helping chondrocytes “clean house” and stay healthy.
Comparing Celastrol to Rapamycin (Another mTOR Inhibitor)
To deepen their findings, the team compared celastrol to rapamycin—a well-known mTOR inhibitor used in research. Both drugs reduced mTOR, but celastrol offered extra benefits:
- It increased phosphorylated PERK (a marker of endoplasmic reticulum, or ER, stress activation). This helps cells adapt to stress instead of dying.
- It decreased cell death markers (caspase 12, or CASP12, and DNA damage-inducible transcript 3, or DDIT3)—meaning fewer chondrocytes were dying.
Even better: Combining celastrol with rapamycin had a synergistic effect. Together, they suppressed mTOR more strongly and boosted autophagy beyond what either drug did alone (statistically significant, with P < 0.05).
Confirming mTOR Is the Key Target
To prove mTOR was essential to celastrol’s effects, the team used two approaches:
-
MHY1485 (an mTOR agonist):
When they added this drug (which activates mTOR) to celastrol, it reversed celastrol’s benefits:- mTOR stayed high.
- Autophagy dropped (P62 increased, LC3-II decreased).
- Cell death markers rose.
This confirmed that celastrol’s effects depend on inhibiting mTOR.
-
mTOR siRNA (gene silencing):
The team used small interfering RNA to “turn off” the mTOR gene in chondrocytes. Both celastrol treatment and mTOR silencing promoted autophagy equally—there was no difference between the two groups. This proved mTOR is celastrol’s key target in OA chondrocytes.
What Does This Mean for OA Treatment?
The study’s conclusions are promising:
- Celastrol protects OA chondrocytes by inhibiting mTOR and boosting autophagy.
- Combining celastrol with rapamycin could be even more effective.
- Pairing celastrol with an mTOR agonist (like MHY1485) cancels out its benefits—so mTOR inhibition is non-negotiable for celastrol to work.
Next Steps
The team plans to test these findings in OA mouse models to see if celastrol’s cell-based benefits translate to living organisms. If successful, this could pave the way for new, targeted treatments for OA.
About the Research Team
This study was led by Siming Dai, Jiankun Fan, Yue Zhang, Zhenyong Hao, Huiming Yu, and Zhiyi Zhang from the Department of Rheumatology and Immunology at The First Affiliated Hospital of Harbin Medical University, along with researchers from Harbin Medical University’s Laboratory of Medical Genetics, Shenzhen Futian Hospital for Rheumatic Diseases, and Harbin Fifth Hospital’s Department of Orthopedic Surgery. It was funded by the National Natural Science Foundation of China (Grants No. 81771749 and 81771748).
Published In
The study appeared in the Chinese Medical Journal in 2022.
doi: 10.1097/CM9.0000000000001552
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