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Updated: May 15, 2025
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis
Yong Gou1,2,3, Chenggui Wang1,2,3, Kejian Fu1,2,3
1Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Background:
The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration in the procedure of osteoarthritis (OA). Mitophagy is responsible for the scavenging of ROS and dysfunctional mitochondria and is considered a key therapeutic target for the treatment of OA. Tiopronin, a classic thiol antioxidant, has been widely studied for the treatment of various oxidative stress-related diseases.
Methods:
The expression of mitophagy (PINK1, PARKIN, and TOMM20) in intact and damaged cartilage of OA patients was analyzed by Western blot and histological analysis. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanism of tiopronin in regulating mitophagy in chondrocytes, and then to find the specific target of tiopronin. The therapeutic effects of tiopronin were evaluated in the OA model induced by destabilisation of the medial meniscus (DMM), chondrocytes degenerative model with the primary chondrocytes from mouse and human cartilage explants experiment. The downstream molecular mechanisms of tiopronin were further investigated by si-RNA knockdown of mitophagy-related proteins.
Results:
The level of mitophagy in cartilage was negatively correlated with the severity of OA. We revealed that tiopronin promoted the anabolism of the extracellular matrix (ECM) of hyaline chondrocytes and alleviates ROS in vitro and in vivo by strengthening mitophagy. Moreover, tiopronin strongly activated the expression of Bnip3, a protein anchored in the mitochondrial membrane, and subsequently enhanced the Pink1/Parkin signaling pathway.
Conclusion:
These findings indicate that the Bnip3-Pink1-Parkin signaling pathway, targeted and activated by tiopronin, plays a key role in inhibiting the progression of OA.
The Translational Potential Of This Article:
As a classical drug in clinic, tiopronin was developed a new therapeutic approach in the treatment in OA via this study. Based the significant and efficient effect of tiopronin in inhibiting the cartilage degermation and delay the progression of OA, it was believed that tiopronin may become an effective therapeutic candidate for OA treatment in clinical settings.
Insights
Tiopronin enhances mitophagy, clearing reactive oxygen species (ROS) and damaged mitochondria to protect cartilage. This study reveals tiopronin’s potential to treat osteoarthritis (OA) by targeting the Bnip3-Pink1-Parkin pathway.
Area of Science:
- Biochemistry
- Cell Biology
- Orthopedics
Background:
- Osteoarthritis (OA) involves chondrocyte mitochondrial dysfunction and reactive oxygen species (ROS) production, leading to cartilage degeneration.
- Mitophagy, the process of clearing damaged mitochondria, is crucial for managing ROS and is a potential therapeutic target for OA.
- Tiopronin, a known thiol antioxidant, has therapeutic applications in diseases linked to oxidative stress.
Purpose of the Study:
- To investigate the role of mitophagy in OA pathogenesis.
- To explore the molecular mechanisms by which tiopronin regulates mitophagy in chondrocytes.
- To evaluate the therapeutic efficacy of tiopronin in preclinical OA models.
Main Methods:
- Analyzed mitophagy marker expression (PINK1, PARKIN, TOMM20) in OA cartilage using Western blot and histology.
- Utilized RNA sequencing (RNA-seq) to identify tiopronin's molecular targets in chondrocytes.
- Assessed tiopronin's effects in an OA mouse model (DMM), a primary chondrocyte model, and human cartilage explants.
- Investigated downstream mechanisms via siRNA knockdown of mitophagy proteins.
Main Results:
- Mitophagy levels negatively correlated with OA severity.
- Tiopronin promoted extracellular matrix (ECM) anabolism and reduced ROS in chondrocytes in vitro and in vivo by enhancing mitophagy.
- Tiopronin activated mitochondrial membrane protein Bnip3, subsequently boosting the Pink1/Parkin signaling pathway.
Conclusions:
- The Bnip3-Pink1-Parkin signaling pathway, activated by tiopronin, is key in preventing OA progression.
- Tiopronin represents a novel therapeutic strategy for OA by targeting mitophagy.
- Tiopronin shows promise as an effective clinical treatment for OA, inhibiting cartilage degradation and delaying disease progression.
