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Regulating obesity-induced osteoarthritis by targeting p53-FOXO3, osteoclast ferroptosis, and mesenchymal stem cell
Chen Zhao1, Keyu Kong1, Pengcheng Liu2
1Department of Orthopedics, Shanghai Key Laboratory of Orthopedics Implant, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Obesity-related osteoarthritis (OA) and the molecular mechanisms governing multiple joint structural changes that occur with obesity are not well understood. This study investigated the progression of obesity in mice and validated the results using human joint samples post-arthroplasty. The results show that obesity is associated with the degeneration of the cartilage layer and abnormal remodeling of the subchondral bone layer, and this occurs alongside aging and DNA damage in chondrocytes, osteoclasts, and stem cells. Regulation of p53-FOXO3 gene loop expression in response to DNA damage effectively inhibits chondrocyte apoptosis, catabolism, and excessive osteoclast differentiation, while the intra-articular delivery of a lentivirus expressing FOXO3 to mouse joints alleviates the progression of OA. The excessive differentiation of subchondral bone marrow osteoclasts is ferroptosis-dependent and driven by the senescence-associated secretory phenotype. The results have identified multiple potential targets for future research into the progression of obesity-related OA.
Insights
Obesity accelerates osteoarthritis by damaging cartilage and bone. Enhancing FOXO3 gene expression in joint cells can inhibit this progression, offering new therapeutic targets for obesity-related joint disease.
Area of Science:
- Biomedical research
- Molecular biology
- Orthopedics
Background:
- Obesity-related osteoarthritis (OA) mechanisms and joint structural changes are poorly understood.
- Existing knowledge gaps hinder effective therapeutic strategies for obesity-induced OA.
Purpose of the Study:
- To investigate the molecular mechanisms of obesity-related OA progression in mice.
- To validate findings in human joint samples.
- To identify potential therapeutic targets for obesity-related OA.
Main Methods:
- Obesity progression was studied in mouse models.
- Human joint samples from post-arthroplasty patients were used for validation.
- Gene expression analysis, cell apoptosis assays, and osteoclast differentiation studies were performed.
- Intra-articular lentiviral delivery of FOXO3 was used in mouse models.
Main Results:
- Obesity is linked to cartilage degeneration and subchondral bone remodeling, associated with aging and DNA damage in joint cells.
- p53-FOXO3 gene loop regulation in response to DNA damage inhibits chondrocyte apoptosis and osteoclast differentiation.
- Intra-articular FOXO3 delivery ameliorated OA progression in mice.
- Subchondral bone marrow osteoclast differentiation is ferroptosis-dependent and driven by senescence-associated secretory phenotype.
Conclusions:
- The p53-FOXO3 pathway is a key regulator in obesity-related OA.
- Targeting ferroptosis and senescence-associated secretory phenotype may offer new avenues for OA treatment.
- FOXO3 delivery shows therapeutic potential for obesity-related osteoarthritis.
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