Regulating obesity-induced osteoarthritis by targeting p53-FOXO3, osteoclast ferroptosis, and mesenchymal stem cell adipogenesis

Chen Zhao, Keyu Kong, Pengcheng Liu, Xuzhuo Chen, Kewei Rong, Pu Zhang, Lei Wang () and Xiaoqing Wang ()
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Chen Zhao: Shanghai Jiao Tong University School of Medicine
Keyu Kong: Shanghai Jiao Tong University School of Medicine
Pengcheng Liu: Shanghai Jiao Tong University School of Medicine
Xuzhuo Chen: Shanghai Jiao Tong University School of Medicine
Kewei Rong: Shanghai Jiao Tong University School of Medicine
Pu Zhang: Shanghai Jiao Tong University School of Medicine
Lei Wang: Shanghai Jiao Tong University School of Medicine
Xiaoqing Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59883-z

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