Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation
Abstract Osteoarthritis is the most prevalent age-related degenerative joint disease and is closely linked to obesity. However, the underlying mechanisms remain unclear. Here we show that altered lipid metabolism in chondrocytes, particularly enhanced fatty acid oxidation (FAO), contributes to osteo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60037-4 |
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| author | Zixuan Mei Kamuran Yilamu Weiyu Ni Panyang Shen Nan Pan Huasen Chen Yingfeng Su Lei Guo Qunan Sun Zhaomei Li Dongdong Huang Xiangqian Fang Shunwu Fan Haitao Zhang Shuying Shen |
| author_facet | Zixuan Mei Kamuran Yilamu Weiyu Ni Panyang Shen Nan Pan Huasen Chen Yingfeng Su Lei Guo Qunan Sun Zhaomei Li Dongdong Huang Xiangqian Fang Shunwu Fan Haitao Zhang Shuying Shen |
| author_sort | Zixuan Mei |
| collection | DOAJ |
| description | Abstract Osteoarthritis is the most prevalent age-related degenerative joint disease and is closely linked to obesity. However, the underlying mechanisms remain unclear. Here we show that altered lipid metabolism in chondrocytes, particularly enhanced fatty acid oxidation (FAO), contributes to osteoarthritis progression. Excessive FAO causes acetyl-CoA accumulation, thereby altering protein-acetylation profiles, where the core FAO enzyme HADHA is hyperacetylated and activated, reciprocally boosting FAO activity and exacerbating OA progression. Mechanistically, elevated FAO reduces AMPK activity, impairs SOX9 phosphorylation, and ultimately promotes its ubiquitination-mediated degradation. Additionally, acetyl-CoA orchestrates epigenetic modulation, affecting multiple cellular processes critical for osteoarthritis pathogenesis, including the transcriptional activation of MMP13 and ADAMTS7. Cartilage-targeted delivery of trimetazidine, an FAO inhibitor and AMPK activator, demonstrates superior efficacy in a mouse model of metabolism-associated post-traumatic osteoarthritis. These findings suggest that targeting chondrocyte-lipid metabolism may offer new therapeutic strategies for osteoarthritis. |
| format | Article |
| id | doaj-art-317de46375b045939bf01fdffa420f56 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-317de46375b045939bf01fdffa420f562025-08-20T03:16:32ZengNature PortfolioNature Communications2041-17232025-05-0116112210.1038/s41467-025-60037-4Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulationZixuan Mei0Kamuran Yilamu1Weiyu Ni2Panyang Shen3Nan Pan4Huasen Chen5Yingfeng Su6Lei Guo7Qunan Sun8Zhaomei Li9Dongdong Huang10Xiangqian Fang11Shunwu Fan12Haitao Zhang13Shuying Shen14Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicinePooling Institute of Translational MedicineDepartment of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Geriatrics, Xiaoshan Geriatric HospitalPooling Institute of Translational MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract Osteoarthritis is the most prevalent age-related degenerative joint disease and is closely linked to obesity. However, the underlying mechanisms remain unclear. Here we show that altered lipid metabolism in chondrocytes, particularly enhanced fatty acid oxidation (FAO), contributes to osteoarthritis progression. Excessive FAO causes acetyl-CoA accumulation, thereby altering protein-acetylation profiles, where the core FAO enzyme HADHA is hyperacetylated and activated, reciprocally boosting FAO activity and exacerbating OA progression. Mechanistically, elevated FAO reduces AMPK activity, impairs SOX9 phosphorylation, and ultimately promotes its ubiquitination-mediated degradation. Additionally, acetyl-CoA orchestrates epigenetic modulation, affecting multiple cellular processes critical for osteoarthritis pathogenesis, including the transcriptional activation of MMP13 and ADAMTS7. Cartilage-targeted delivery of trimetazidine, an FAO inhibitor and AMPK activator, demonstrates superior efficacy in a mouse model of metabolism-associated post-traumatic osteoarthritis. These findings suggest that targeting chondrocyte-lipid metabolism may offer new therapeutic strategies for osteoarthritis.https://doi.org/10.1038/s41467-025-60037-4 |
| spellingShingle | Zixuan Mei Kamuran Yilamu Weiyu Ni Panyang Shen Nan Pan Huasen Chen Yingfeng Su Lei Guo Qunan Sun Zhaomei Li Dongdong Huang Xiangqian Fang Shunwu Fan Haitao Zhang Shuying Shen Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation Nature Communications |
| title | Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation |
| title_full | Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation |
| title_fullStr | Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation |
| title_full_unstemmed | Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation |
| title_short | Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation |
| title_sort | chondrocyte fatty acid oxidation drives osteoarthritis via sox9 degradation and epigenetic regulation |
| url | https://doi.org/10.1038/s41467-025-60037-4 |
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