Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway
Background: Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence...
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Elsevier
2025-09-01
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| Series: | Journal of Orthopaedic Translation |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214031X25001160 |
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| author | Xiaoyu Jin Xunhao Wang Siyu Xu Nuo Xu Ziwei Wang Chunqing Hu Wei Liu Zhaofeng Zhang Xiyu Liu Jingjing Fan Ruiyang Jiang Rui Wu Zhongyang Lv Dongquan Shi |
| author_facet | Xiaoyu Jin Xunhao Wang Siyu Xu Nuo Xu Ziwei Wang Chunqing Hu Wei Liu Zhaofeng Zhang Xiyu Liu Jingjing Fan Ruiyang Jiang Rui Wu Zhongyang Lv Dongquan Shi |
| author_sort | Xiaoyu Jin |
| collection | DOAJ |
| description | Background: Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 (Gfi1) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA. Methods: The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress Gfi1 to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing Gfi1 (AAV-Gfi1). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis. Results: The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, Gfi1 knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, lipid ROS and Fe2+ accumulation. The upregulation of ferroptotic driver (Cox2, Acsl4) and catabolic marker (Mmp13) and downregulation of ferroptotic suppressors (Gpx4, Fth1, Slc7a11) and anabolic marker (Col II) were also observed in TBHP-induced chondrocytes by Gfi1 knockdown. On the contrary, Gfi1 overexpression showed anti-ferroptotic effect in TBHP-induced chondrocytes. Intra-articular injection of AAV-Gfi1 evidently alleviated cartilage degeneration by resisting ferroptosis and preserving the anabolism-catabolism homeostasis in OA cartilages. Comprehensive evaluation of subchondral bone sclerosis, osteophyte formation, synovitis and behavior performance further validated that Gfi1 overexpression ameliorated OA progression. Mechanistically, MAPK signaling pathway was identified as the key downstream mediator of Gfi1 exerting anti-ferroptotic role in OA. Conclusion: Gfi1 is downregulated in OA and its overexpression ameliorates OA progression by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway. The translational potential of this article: This study identifies Gfi1 as a novel therapeutic anti-ferroptotic target for cartilage degeneration, providing more clues for optimizing OA treatment strategies in clinical practice. |
| format | Article |
| id | doaj-art-77f3a5f6dba4417c9cbc42ae1c27fe24 |
| institution | Kabale University |
| issn | 2214-031X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Journal of Orthopaedic Translation |
| spelling | doaj-art-77f3a5f6dba4417c9cbc42ae1c27fe242025-08-20T03:58:36ZengElsevierJournal of Orthopaedic Translation2214-031X2025-09-015410111410.1016/j.jot.2025.07.003Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathwayXiaoyu Jin0Xunhao Wang1Siyu Xu2Nuo Xu3Ziwei Wang4Chunqing Hu5Wei Liu6Zhaofeng Zhang7Xiyu Liu8Jingjing Fan9Ruiyang Jiang10Rui Wu11Zhongyang Lv12Dongquan Shi13Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaSuzhou Medical College of Soochow University, Suzhou 215031, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDivision of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, ChinaDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu, China; Corresponding author.Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China; Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China; Corresponding author. Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.Background: Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 (Gfi1) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA. Methods: The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress Gfi1 to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing Gfi1 (AAV-Gfi1). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis. Results: The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, Gfi1 knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, lipid ROS and Fe2+ accumulation. The upregulation of ferroptotic driver (Cox2, Acsl4) and catabolic marker (Mmp13) and downregulation of ferroptotic suppressors (Gpx4, Fth1, Slc7a11) and anabolic marker (Col II) were also observed in TBHP-induced chondrocytes by Gfi1 knockdown. On the contrary, Gfi1 overexpression showed anti-ferroptotic effect in TBHP-induced chondrocytes. Intra-articular injection of AAV-Gfi1 evidently alleviated cartilage degeneration by resisting ferroptosis and preserving the anabolism-catabolism homeostasis in OA cartilages. Comprehensive evaluation of subchondral bone sclerosis, osteophyte formation, synovitis and behavior performance further validated that Gfi1 overexpression ameliorated OA progression. Mechanistically, MAPK signaling pathway was identified as the key downstream mediator of Gfi1 exerting anti-ferroptotic role in OA. Conclusion: Gfi1 is downregulated in OA and its overexpression ameliorates OA progression by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway. The translational potential of this article: This study identifies Gfi1 as a novel therapeutic anti-ferroptotic target for cartilage degeneration, providing more clues for optimizing OA treatment strategies in clinical practice.http://www.sciencedirect.com/science/article/pii/S2214031X25001160OsteoarthritisFerroptosisChondrocyteGfi1MAPK |
| spellingShingle | Xiaoyu Jin Xunhao Wang Siyu Xu Nuo Xu Ziwei Wang Chunqing Hu Wei Liu Zhaofeng Zhang Xiyu Liu Jingjing Fan Ruiyang Jiang Rui Wu Zhongyang Lv Dongquan Shi Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway Journal of Orthopaedic Translation Osteoarthritis Ferroptosis Chondrocyte Gfi1 MAPK |
| title | Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway |
| title_full | Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway |
| title_fullStr | Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway |
| title_full_unstemmed | Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway |
| title_short | Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway |
| title_sort | growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of mapk signaling pathway |
| topic | Osteoarthritis Ferroptosis Chondrocyte Gfi1 MAPK |
| url | http://www.sciencedirect.com/science/article/pii/S2214031X25001160 |
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