Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis
Abstract Highly conserved homeobox genes are closely related to bone formation during embryogenesis, while their role in adult bone resorption remains unclear. In this study, we found that the homeobox gene MSX2 actively participates bone metabolism. Myeloid-specific Msx2 deficiency safeguards bone...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61938-0 |
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| author | Qingliang Ma Shiyu Wang Hong Xue Linhui Ni Putao Yuan Yang Shen Bingjie Zheng Qingqing Wang Jiateng Zhang Haoming Wang Hongwei Xie Chao Jiang An Qin Shunwu Fan Ziang Xie Zhiwei Jie |
| author_facet | Qingliang Ma Shiyu Wang Hong Xue Linhui Ni Putao Yuan Yang Shen Bingjie Zheng Qingqing Wang Jiateng Zhang Haoming Wang Hongwei Xie Chao Jiang An Qin Shunwu Fan Ziang Xie Zhiwei Jie |
| author_sort | Qingliang Ma |
| collection | DOAJ |
| description | Abstract Highly conserved homeobox genes are closely related to bone formation during embryogenesis, while their role in adult bone resorption remains unclear. In this study, we found that the homeobox gene MSX2 actively participates bone metabolism. Myeloid-specific Msx2 deficiency safeguards bone mass under physiological and pathological conditions. Loss of Msx2 acts as a “brake” in the fusion fate of osteoclasts, resulting in a larger population of pre-osteoclasts. Pre-osteoclasts secrete platelet-derived growth factor-BB (PDGF-BB), which promotes angiogenesis-mediated bone formation. Mechanistically, MSX2 directly binds to the vital osteoclastogenic transcription factor PU.1 and protects it from FBXW7-mediated ubiquitination degradation. Msx2 and Fbxw7 double knockout mitigated the protective effect of MSX2 deficiency on bone mass. Finally, we identified a natural compound, morusinol, that specifically destroys the combination of MSX2 and PU.1, promoting PU.1 degradation and attenuating ovariectomy-induced bone loss. Overall, our results demonstrate that targeting Msx2 is a promising anabolic therapy for osteoporosis. |
| format | Article |
| id | doaj-art-5ee8992c13ca4dd8b6181cb7d121faae |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5ee8992c13ca4dd8b6181cb7d121faae2025-08-20T03:43:00ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-61938-0Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosisQingliang Ma0Shiyu Wang1Hong Xue2Linhui Ni3Putao Yuan4Yang Shen5Bingjie Zheng6Qingqing Wang7Jiateng Zhang8Haoming Wang9Hongwei Xie10Chao Jiang11An Qin12Shunwu Fan13Ziang Xie14Zhiwei Jie15Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract Highly conserved homeobox genes are closely related to bone formation during embryogenesis, while their role in adult bone resorption remains unclear. In this study, we found that the homeobox gene MSX2 actively participates bone metabolism. Myeloid-specific Msx2 deficiency safeguards bone mass under physiological and pathological conditions. Loss of Msx2 acts as a “brake” in the fusion fate of osteoclasts, resulting in a larger population of pre-osteoclasts. Pre-osteoclasts secrete platelet-derived growth factor-BB (PDGF-BB), which promotes angiogenesis-mediated bone formation. Mechanistically, MSX2 directly binds to the vital osteoclastogenic transcription factor PU.1 and protects it from FBXW7-mediated ubiquitination degradation. Msx2 and Fbxw7 double knockout mitigated the protective effect of MSX2 deficiency on bone mass. Finally, we identified a natural compound, morusinol, that specifically destroys the combination of MSX2 and PU.1, promoting PU.1 degradation and attenuating ovariectomy-induced bone loss. Overall, our results demonstrate that targeting Msx2 is a promising anabolic therapy for osteoporosis.https://doi.org/10.1038/s41467-025-61938-0 |
| spellingShingle | Qingliang Ma Shiyu Wang Hong Xue Linhui Ni Putao Yuan Yang Shen Bingjie Zheng Qingqing Wang Jiateng Zhang Haoming Wang Hongwei Xie Chao Jiang An Qin Shunwu Fan Ziang Xie Zhiwei Jie Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis Nature Communications |
| title | Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis |
| title_full | Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis |
| title_fullStr | Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis |
| title_full_unstemmed | Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis |
| title_short | Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis |
| title_sort | targeting msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre clinical models of osteoporosis |
| url | https://doi.org/10.1038/s41467-025-61938-0 |
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