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Chondrogenic Differentiation Induction of Adipose-derived Stem Cells by Centrifugal Gravity
Published on: February 24, 2017
Doxorubicin suppresses chondrocyte differentiation by stimulating ROS production
Cheng Wu1, Jiayi Luo1, Yuanxin Liu2
1Department of Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province 550004, PR China; Department of Sports Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province 550004, PR China.
Background:
Doxorubicin (DOX) is widely used as an effective chemotherapy agent in human cancer. Our study aimed to explore the specific mechanism of DOX in osteoarthritis (OA).
Methods:
A mouse OA model was established by destabilizing the medial meniscus (DMM), and the role of DOX was determined by intraperitoneally injecting 5 or 10 mg/kg DOX. The expression of collagen type-II (Col-2) was detected by immunohistochemistry staining, and the expression of plasma interleukin (IL)-6 (IL-6), IL-1beta (IL-1β), and tumor necrosis factor (TNF)-alpha (TNF-α) was evaluated by specific ELISA kits, and the expression of Sry-related HMG box 9 (SOX-9) was detected by western blot. Bone marrow mesenchymal stem cells (BMMSCs) were used to explore the mechanism of DOX in vitro. Reactive oxygen species (ROS) production was determined by flow cytometry. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assay. Chondrocyte differentiation was evaluated by Alcian blue staining assay. The expression of chondrocyte differentiation-related markers was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR).
Results:
DOX exposure exacerbated OA progression and inhibited chondrocyte differentiation of BMMSCs. DOX also increased ROS production in BMMSCs. Meanwhile, DOX further increased the elevation of plasma IL-6, IL-1β and TNF-α induced by DMM and obviously reduced the expression of chondrocyte differentiation-related markers, including collagen type II a1 (Col2A1), collagen type X alpha 1 (Col10A1), and aggrecan. Moreover, ROS scavengers NAC and MitoQ efficiently alleviated DOX toxicity, including ROS production and chondrocyte differentiation in BMMSCs.
Conclusion:
Our study revealed that DOX suppressed chondrocyte differentiation by stimulating ROS production, providing a novel theoretical strategy for the clinical treatment of OA caused by DOX.
Insights
Doxorubicin (DOX) worsens osteoarthritis (OA) by increasing oxidative stress and inhibiting chondrocyte differentiation. Antioxidants can reverse these harmful effects, offering a new treatment strategy for DOX-induced OA.
Area of Science:
- Biomedical Science
- Cell Biology
- Pharmacology
Background:
- Doxorubicin (DOX) is a potent chemotherapy drug with known side effects.
- Osteoarthritis (OA) is a degenerative joint disease affecting millions worldwide.
- The specific mechanisms by which DOX impacts OA remain incompletely understood.
Purpose of the Study:
- To investigate the role and mechanism of Doxorubicin (DOX) in the progression of osteoarthritis (OA).
- To explore the effects of DOX on chondrocyte differentiation and oxidative stress in an OA mouse model.
- To evaluate potential therapeutic interventions for DOX-induced OA.
Main Methods:
- An osteoarthritis (OA) mouse model was induced using destabilization of the medial meniscus (DMM).
- Doxorubicin (DOX) was administered intraperitoneally, and its effects on chondrocyte differentiation markers (Col-2, SOX-9), inflammatory cytokines (IL-6, IL-1β, TNF-α), and reactive oxygen species (ROS) were assessed.
- In vitro studies using bone marrow mesenchymal stem cells (BMMSCs) evaluated DOX's impact on cell viability, chondrogenesis, and ROS production, with ROS scavengers (NAC, MitoQ) used for mechanistic insights.
Main Results:
- Doxorubicin (DOX) exposure significantly exacerbated OA progression in the DMM model.
- DOX treatment inhibited chondrocyte differentiation in bone marrow mesenchymal stem cells (BMMSCs) and increased reactive oxygen species (ROS) production.
- DOX amplified DMM-induced elevations in plasma IL-6, IL-1β, and TNF-α, while reducing key chondrogenic markers (Col2A1, Col10A1, aggrecan).
- The administration of ROS scavengers (NAC, MitoQ) effectively mitigated DOX-induced toxicity, including ROS overproduction and impaired chondrocyte differentiation.
Conclusions:
- Doxorubicin (DOX) suppresses chondrocyte differentiation in osteoarthritis (OA) primarily by stimulating reactive oxygen species (ROS) production.
- This study provides a novel theoretical basis for developing clinical strategies to treat OA associated with Doxorubicin (DOX) therapy.
- Targeting ROS may offer a promising therapeutic avenue for managing Doxorubicin (DOX)-induced joint damage.
