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Astragalus polysaccharide alleviates oxidative stress and senescence in chondrocytes in osteoarthritis via
Kai Chen1, Chaoren Qin1, Chenfei Ji2
1The Yancheng Clinical College of Xuzhou Medical University, People's Republic of China; Department of Orthopedics, The First People's Hospital of Yancheng, People's Republic of China.
Abstract:
The treatment of osteoarthritis (OA) remains challenging, with oxidative stress in the cartilage emerging as a key therapeutic target. This study investigates how Astragalus polysaccharide (APS) exerts antioxidant effects in OA using in vivo and in vitro models. In mice, APS mitigates OA progression following surgical destabilization of the medial meniscus (DMM) and protects against oxidative damage. Immunofluorescence analysis revealed decreased thioredoxin (TXN) expression in DMM cartilage, which was restored by APS. APS preserved mitochondrial function, redox balance, and matrix synthesis in chondrocytes in vitro while suppressing metalloproteinase expression. APS also reduced senescence markers (p53, p21INK4a, and p16), DNA damage, and β-galactosidase activity in tert-butyl hydroperoxide (tBHP)-treated chondrocytes. TXN knockdown significantly diminishes the protective effects of APS Further analysis showed that ATF4 overexpression supports the GCN2-ATF4 pathway's involvement in APS. GCN2 inhibition using GCN2iB reduced the regulatory impact of APS on TXN, indicating the crucial role GCN2 in APS-mediated protection. These findings demonstrated that APS protects chondrocytes from oxidative stress and senescence in OA via the GCN2/TXN pathway, suggesting its potential as a therapeutic agent for OA.
Insights
Astragalus polysaccharide (APS) combats osteoarthritis by reducing oxidative stress and cellular senescence in cartilage. It functions through the GCN2/thioredoxin pathway, offering potential as a novel OA therapeutic.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Osteoarthritis (OA) poses significant treatment challenges, with oxidative stress identified as a critical factor in cartilage degradation.
- Identifying novel therapeutic targets and agents to combat OA progression is a key research priority.
Purpose of the Study:
- To investigate the antioxidant and chondroprotective mechanisms of Astragalus polysaccharide (APS) in osteoarthritis.
- To elucidate the role of the GCN2/thioredoxin (TXN) pathway in APS-mediated protection against OA-related cellular damage.
Main Methods:
- In vivo studies utilized a surgical destabilization of the medial meniscus (DMM) mouse model of OA.
- In vitro experiments involved chondrocytes treated with tert-butyl hydroperoxide (tBHP) to induce oxidative stress and senescence.
- Immunofluorescence, Western blotting, and biochemical assays were employed to assess cellular damage, mitochondrial function, matrix synthesis, and pathway activation (GCN2, ATF4, TXN).
Main Results:
- APS treatment mitigated OA progression and oxidative damage in DMM mice, restoring thioredoxin (TXN) expression.
- In vitro, APS preserved chondrocyte mitochondrial function, redox balance, and matrix synthesis while suppressing metalloproteinase expression.
- APS reduced senescence markers, DNA damage, and β-galactosidase activity in chondrocytes. The protective effects were dependent on TXN and involved the GCN2/ATF4 pathway.
Conclusions:
- Astragalus polysaccharide (APS) demonstrates significant chondroprotective effects against oxidative stress and senescence in osteoarthritis models.
- The GCN2/TXN pathway is crucial for APS-mediated protection, highlighting a novel therapeutic mechanism for OA.
- APS shows promise as a potential therapeutic agent for treating osteoarthritis.
