IADR Abstract Archives
Hybrid Joint Fluid Extracellular Vesicles Drive Metabolic Damage Impairing Chondrogenesis
Objectives: This study aimed to elucidate the role of joint fluid extracellular vesicles (EVs) in regulating the metabolic homeostasis of degenerative cartilage and uncover the mechanisms behind the limited chondrocyte regenerative capacity in temporomandibular joint osteoarthritis (TMJOA). Thus developing metabolic targeting strategies for OA.
Methods: 1. EVs were isolated from the joint fluid of TMJOA patients and controls. They were characterized by the proteomic, immuno-electron microscope, and nano-flow cytometry to identify a subgroup of hybrid EVs (hEVs) co-expressing macrophage and collagen markers correlated with TMJOA progress.
2. The MIA-induced rat TMJOA model was used to test the effect of hEVs on TMJOA.
3. An in vitro model of hEVs was developed to explore their impact and underlying mechanism on mitochondrial damage, metabolic reprogramming, TCA cycle metabolite alteration, and cell fate direction of chondrocytes. The effect of unveiled metabolic targets was verified in the rat TMJOA models.
Results: 1. Endogenous hEVs from macrophages and chondrocytes accumulate in joint fluid of OA patients, correlating with disease progression.
2. Intra-articular hEVs injection halts chondrogenic differentiation and increases mitochondrial defects and senescent chondrocytes in TMJOA rats.
3. hEVs enhance inflammation-induced glycolysis in cartilage stem/progenitor cells (CSPCs) and trigger irreversible mitochondrial fragmentation. Concurrently, they decrease mitochondrial membrane potential in an ANT1-dependent way, perturb TCA cycle metabolites, leading to cellular senescence and chondrogenic dysfunction.
4. A combination therapy using an ANT1 inhibitor supplying metabolites corrected hEVs-induced metabolic and cell fate reprogramming, ultimately restoring impaired chondrogenesis and increased senescence in CSPCs and rat TMJOA models.
Conclusions: For the first time, this study identified a subtype of humoral hybrid EVs in TMJOA patients derived from multiple populations of cells. These hEVs contribute to irreversible mitochondria damage and cellular senescence of CSPCs, paving the way for developing new metabolically targeted strategies to treat OA.
Methods: 1. EVs were isolated from the joint fluid of TMJOA patients and controls. They were characterized by the proteomic, immuno-electron microscope, and nano-flow cytometry to identify a subgroup of hybrid EVs (hEVs) co-expressing macrophage and collagen markers correlated with TMJOA progress.
2. The MIA-induced rat TMJOA model was used to test the effect of hEVs on TMJOA.
3. An in vitro model of hEVs was developed to explore their impact and underlying mechanism on mitochondrial damage, metabolic reprogramming, TCA cycle metabolite alteration, and cell fate direction of chondrocytes. The effect of unveiled metabolic targets was verified in the rat TMJOA models.
Results: 1. Endogenous hEVs from macrophages and chondrocytes accumulate in joint fluid of OA patients, correlating with disease progression.
2. Intra-articular hEVs injection halts chondrogenic differentiation and increases mitochondrial defects and senescent chondrocytes in TMJOA rats.
3. hEVs enhance inflammation-induced glycolysis in cartilage stem/progenitor cells (CSPCs) and trigger irreversible mitochondrial fragmentation. Concurrently, they decrease mitochondrial membrane potential in an ANT1-dependent way, perturb TCA cycle metabolites, leading to cellular senescence and chondrogenic dysfunction.
4. A combination therapy using an ANT1 inhibitor supplying metabolites corrected hEVs-induced metabolic and cell fate reprogramming, ultimately restoring impaired chondrogenesis and increased senescence in CSPCs and rat TMJOA models.
Conclusions: For the first time, this study identified a subtype of humoral hybrid EVs in TMJOA patients derived from multiple populations of cells. These hEVs contribute to irreversible mitochondria damage and cellular senescence of CSPCs, paving the way for developing new metabolically targeted strategies to treat OA.