DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis
Abstract Osteoporosis (OP) is a common and fracture-prone skeletal disease characterized by deteriorated trabecular microstructure and pathologically involving various forms of regulated bone cell death. However, the exact role, cellular nature and regulatory mechanisms of ferroptosis in OP are not...
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Nature Publishing Group
2024-12-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00365-1 |
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| author | Binjia Ruan Jian Dong Fanhao Wei Zhiqiang Huang Bin Yang Lijun Zhang Chuling Li Hui Dong Wangsen Cao Hongwei Wang Yongxiang Wang |
| author_facet | Binjia Ruan Jian Dong Fanhao Wei Zhiqiang Huang Bin Yang Lijun Zhang Chuling Li Hui Dong Wangsen Cao Hongwei Wang Yongxiang Wang |
| author_sort | Binjia Ruan |
| collection | DOAJ |
| description | Abstract Osteoporosis (OP) is a common and fracture-prone skeletal disease characterized by deteriorated trabecular microstructure and pathologically involving various forms of regulated bone cell death. However, the exact role, cellular nature and regulatory mechanisms of ferroptosis in OP are not fully understood. Here, we reported that OP femurs from ovariectomized (Ovx) mice exhibited pronounced iron deposition, ferroptosis, and transcriptional suppression of a key anti-ferroptotic factor GPX4 (glutathione peroxidase 4). GPX4 suppression was accompanied by hypermethylation of the Gpx4 promoter and an increase in DNA methyltransferases DNMT1/3a/3b and was transcriptionally promoted by repressive KLF5 and the transcriptional corepressors NCoR and SnoN. Conversely, DNMT inhibition with SGI-1027 reversed promoter hypermethylation, GPX4 suppression and ferroptotic osteoporosis. In cultured primary bone cells, ferric ammonium citrate (FAC) mimicking iron loading similarly induced GPX4 suppression and ferroptosis in osteoblasts but not in osteoclasts, which were rescued by siRNA-mediated individual knockdown of DNMT 1/3a/3b. Intriguingly, SGI-1027 alleviated the ferroptotic changes caused by FAC, but not by a GPX4 inactivator RSL3. More importantly, we generated a strain of osteoblast-specific Gpx4 haplo-deficient mice Gpx4 Ob+/− that developed spontaneous and more severe ferroptotic OP alterations after Ovx operation, and showed that GPX4 inactivation by RSL3 or semi-knockout in osteoblasts largely abolished the anti-ferroptotic and osteoprotective effects of SGI-1027. Taken together, our data suggest that GPX4 epigenetic suppression caused by DNMT aberration and the resulting osteoblastic ferroptosis contribute significantly to OP pathogenesis, and that the strategies preserving GPX4 by DNMT intervention are potentially effective to treat OP and related bone disorders. |
| format | Article |
| id | doaj-art-ded2b0926e8349c48c1412b3d5bf89a6 |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-ded2b0926e8349c48c1412b3d5bf89a62024-12-08T12:21:42ZengNature Publishing GroupBone Research2095-62312024-12-0112111410.1038/s41413-024-00365-1DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosisBinjia Ruan0Jian Dong1Fanhao Wei2Zhiqiang Huang3Bin Yang4Lijun Zhang5Chuling Li6Hui Dong7Wangsen Cao8Hongwei Wang9Yongxiang Wang10Department of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityDepartment of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityNanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine & State Key Laboratory of Analytical Chemistry for Life ScienceDepartment of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityNanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine & State Key Laboratory of Analytical Chemistry for Life ScienceDepartment of Respiratory Medicine, Jinling Hospital, Affiliated Hospital of Nanjing University Medical SchoolDepartment of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityNanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine & State Key Laboratory of Analytical Chemistry for Life ScienceDepartment of Orthopedics, Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing UniversityAbstract Osteoporosis (OP) is a common and fracture-prone skeletal disease characterized by deteriorated trabecular microstructure and pathologically involving various forms of regulated bone cell death. However, the exact role, cellular nature and regulatory mechanisms of ferroptosis in OP are not fully understood. Here, we reported that OP femurs from ovariectomized (Ovx) mice exhibited pronounced iron deposition, ferroptosis, and transcriptional suppression of a key anti-ferroptotic factor GPX4 (glutathione peroxidase 4). GPX4 suppression was accompanied by hypermethylation of the Gpx4 promoter and an increase in DNA methyltransferases DNMT1/3a/3b and was transcriptionally promoted by repressive KLF5 and the transcriptional corepressors NCoR and SnoN. Conversely, DNMT inhibition with SGI-1027 reversed promoter hypermethylation, GPX4 suppression and ferroptotic osteoporosis. In cultured primary bone cells, ferric ammonium citrate (FAC) mimicking iron loading similarly induced GPX4 suppression and ferroptosis in osteoblasts but not in osteoclasts, which were rescued by siRNA-mediated individual knockdown of DNMT 1/3a/3b. Intriguingly, SGI-1027 alleviated the ferroptotic changes caused by FAC, but not by a GPX4 inactivator RSL3. More importantly, we generated a strain of osteoblast-specific Gpx4 haplo-deficient mice Gpx4 Ob+/− that developed spontaneous and more severe ferroptotic OP alterations after Ovx operation, and showed that GPX4 inactivation by RSL3 or semi-knockout in osteoblasts largely abolished the anti-ferroptotic and osteoprotective effects of SGI-1027. Taken together, our data suggest that GPX4 epigenetic suppression caused by DNMT aberration and the resulting osteoblastic ferroptosis contribute significantly to OP pathogenesis, and that the strategies preserving GPX4 by DNMT intervention are potentially effective to treat OP and related bone disorders.https://doi.org/10.1038/s41413-024-00365-1 |
| spellingShingle | Binjia Ruan Jian Dong Fanhao Wei Zhiqiang Huang Bin Yang Lijun Zhang Chuling Li Hui Dong Wangsen Cao Hongwei Wang Yongxiang Wang DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis Bone Research |
| title | DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis |
| title_full | DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis |
| title_fullStr | DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis |
| title_full_unstemmed | DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis |
| title_short | DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis |
| title_sort | dnmt aberration incurred gpx4 suppression prompts osteoblast ferroptosis and osteoporosis |
| url | https://doi.org/10.1038/s41413-024-00365-1 |
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