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Published on: July 26, 2022
Engineered exosomal miR140 modulates mitophagy of chondrocytes through targeting CAPN1 to alleviate osteoarthritis
Yuan Liu1,2, Kai Huang1,2, Sheng-Liang Zhou1
1Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
Abstract:
Osteoarthritis (OA) is a prevalent degenerative disease involving mitophagy dysfunction of chondrocytes. As OA progresses, miR140 expression in chondrocytes decreases, and its therapeutic potential has shown protective effects. However, the variation in mitophagy across different stages of OA in human chondrocytes, as well as the role of miR140 in modulating mitophagy, have remained insufficiently elucidated. In this study, we observed that mitochondrial morphology deteriorates with OA progression, from mild swelling in the early stage of OA (E-OA) to disrupted cristae in the mid-to-late stage of OA (ML-OA). Mitophagy levels were mildly elevated in E-OA chondrocytes compared with normal controls, whilst ML-OA chondrocytes exhibited significantly reduced and impaired mitophagy. Notably, miR140 was found to down-regulate CAPN1, an intracellular cysteine protease affecting mitochondrial and lysosomal membranes. Targeting the miR140/CAPN1 axis was revealed to improve mitochondrial morphology, decrease reactive oxygen species (ROS) accumulation, and promote mitophagy in chondrocytes. To further overcome the inherent instability and limited bioavailability of miR140 when administered directly, engineered exosomes overexpressing miR140 derived from human urine-derived stem cells (hUSCs-140-Exos) were constructed. In vitro, hUSCs-140-Exos were demonstrated to promote mitophagy and preserve mitochondrial function. Moreover, intra-articular injection of hUSCs-140-Exos in vivo effectively delivered miR140 to OA chondrocytes, resulting in improved gait, restoration of subchondral bone structure, and mitigation of OA progression. Overall, this study provides a novel and promising strategy for OA treatment, demonstrating significant therapeutic potential.
Insights
This study reveals that miR140 can restore mitophagy in osteoarthritis (OA) chondrocytes by down-regulating CAPN1. Engineered exosomes delivering miR140 show promise for treating OA by improving mitochondrial function and mitigating disease progression.
Area of Science:
- Biomedical research
- Cell biology
- Regenerative medicine
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by chondrocyte dysfunction, specifically impaired mitophagy.
- MicroRNA-140 (miR140) levels decrease with OA progression, and it exhibits protective effects, but its role in modulating mitophagy in OA remains unclear.
- Mitochondrial morphology and mitophagy dysfunction worsen as OA progresses in human chondrocytes.
Purpose of the Study:
- To investigate the variation in mitophagy across different stages of OA in human chondrocytes.
- To elucidate the role of miR140 in modulating chondrocyte mitophagy.
- To develop a novel therapeutic strategy for OA using miR140 delivery.
Main Methods:
- Analysis of mitochondrial morphology and mitophagy levels in early-stage OA (E-OA) and mid-to-late-stage OA (ML-OA) human chondrocytes.
- Investigating the regulatory relationship between miR140 and CAPN1 (calpain 1).
- Engineering human urine-derived stem cell-derived exosomes overexpressing miR140 (hUSCs-140-Exos) for in vitro and in vivo delivery.
Main Results:
- Mitochondrial morphology deteriorates from E-OA to ML-OA, with reduced mitophagy in ML-OA chondrocytes.
- miR140 directly down-regulates CAPN1, a protease impacting mitochondrial membranes.
- Targeting the miR140/CAPN1 axis improved mitochondrial morphology, reduced reactive oxygen species (ROS), and promoted mitophagy.
- hUSCs-140-Exos effectively delivered miR140, enhanced mitophagy, preserved mitochondrial function, and mitigated OA progression in vivo.
Conclusions:
- The miR140/CAPN1 axis is a key regulator of mitophagy in OA chondrocytes.
- Engineered exosomes (hUSCs-140-Exos) represent a promising, stable delivery vehicle for miR140 in OA therapy.
- This study presents a novel exosome-based therapeutic strategy with significant potential for treating osteoarthritis.
