Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2
Abstract The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis. Nuclear receptors (NRs) are now understood to be crucial in bone physiology and pathology. However, the function of the Farnesoid X receptor (FXR), a member of the NR fa...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00394-w |
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| author | Qi Dong Haoyuan Fu Wenxiao Li Xinyu Ji Yingchao Yin Yiran Zhang Yanbo Zhu Guoqiang Li Huiyang Jia Heng Zhang Haofei Wang Jinglue Hu Ganggang Wang Zhihao Wu Yingze Zhang Sujuan Xu Zhiyong Hou |
| author_facet | Qi Dong Haoyuan Fu Wenxiao Li Xinyu Ji Yingchao Yin Yiran Zhang Yanbo Zhu Guoqiang Li Huiyang Jia Heng Zhang Haofei Wang Jinglue Hu Ganggang Wang Zhihao Wu Yingze Zhang Sujuan Xu Zhiyong Hou |
| author_sort | Qi Dong |
| collection | DOAJ |
| description | Abstract The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis. Nuclear receptors (NRs) are now understood to be crucial in bone physiology and pathology. However, the function of the Farnesoid X receptor (FXR), a member of the NR family, in regulating bone homeostasis remains incompletely understood. In this study, in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells (BMSCs) and osteoblasts due to impaired osteoblast differentiation. Mechanistically, FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination, thereby promoting osteogenic activity in BMSCs. Moreover, activated FXR could directly bind to the Thoc6 promoter, suppressing its expression. The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6. Additionally, Obeticholic acid (OCA), an orally available FXR agonist, could ameliorate bone loss in an ovariectomy (OVX)-induced osteoporotic mouse model. Taken together, our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis. |
| format | Article |
| id | doaj-art-8ea43321ee52449cbad413478585ee30 |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-8ea43321ee52449cbad413478585ee302025-02-02T12:12:37ZengNature Publishing GroupBone Research2095-62312025-01-0113111610.1038/s41413-024-00394-wNuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2Qi Dong0Haoyuan Fu1Wenxiao Li2Xinyu Ji3Yingchao Yin4Yiran Zhang5Yanbo Zhu6Guoqiang Li7Huiyang Jia8Heng Zhang9Haofei Wang10Jinglue Hu11Ganggang Wang12Zhihao Wu13Yingze Zhang14Sujuan Xu15Zhiyong Hou16Department of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Cardiology, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversitySchool of Medicine, Nankai UniversityHebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Hebei Food Inspection and Research InstituteDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityOrthopaedic Research Institute of Hebei Province, Third Hospital of Hebei Medical UniversityPudong Hospital, Fudan UniversitySchool of Preclinical Medicine, Wannan Medical CollegeDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityDepartment of Orthopedic Surgery, Third Hospital of Hebei Medical UniversityAbstract The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis. Nuclear receptors (NRs) are now understood to be crucial in bone physiology and pathology. However, the function of the Farnesoid X receptor (FXR), a member of the NR family, in regulating bone homeostasis remains incompletely understood. In this study, in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells (BMSCs) and osteoblasts due to impaired osteoblast differentiation. Mechanistically, FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination, thereby promoting osteogenic activity in BMSCs. Moreover, activated FXR could directly bind to the Thoc6 promoter, suppressing its expression. The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6. Additionally, Obeticholic acid (OCA), an orally available FXR agonist, could ameliorate bone loss in an ovariectomy (OVX)-induced osteoporotic mouse model. Taken together, our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.https://doi.org/10.1038/s41413-024-00394-w |
| spellingShingle | Qi Dong Haoyuan Fu Wenxiao Li Xinyu Ji Yingchao Yin Yiran Zhang Yanbo Zhu Guoqiang Li Huiyang Jia Heng Zhang Haofei Wang Jinglue Hu Ganggang Wang Zhihao Wu Yingze Zhang Sujuan Xu Zhiyong Hou Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 Bone Research |
| title | Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 |
| title_full | Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 |
| title_fullStr | Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 |
| title_full_unstemmed | Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 |
| title_short | Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 |
| title_sort | nuclear farnesoid x receptor protects against bone loss by driving osteoblast differentiation through stabilizing runx2 |
| url | https://doi.org/10.1038/s41413-024-00394-w |
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