Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes
Abstract Type 2 diabetes mellitus (T2DM) is associated with an elevated fracture risk and impaired healing, but the periosteum’s role in delayed repair remains unclear. In db/db mice, both trabecular and cortical bone mass were reduced, with single-cell RNA sequencing revealing downregulation of the...
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BMC
2025-08-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02349-y |
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| author | Xing Ji Jiahao Luo Yangxun He Xinhua Hu Taotao Xu Yuanlong Wang Sijun Pan Jiali Yao Weiwei Hu Ximei Wu |
| author_facet | Xing Ji Jiahao Luo Yangxun He Xinhua Hu Taotao Xu Yuanlong Wang Sijun Pan Jiali Yao Weiwei Hu Ximei Wu |
| author_sort | Xing Ji |
| collection | DOAJ |
| description | Abstract Type 2 diabetes mellitus (T2DM) is associated with an elevated fracture risk and impaired healing, but the periosteum’s role in delayed repair remains unclear. In db/db mice, both trabecular and cortical bone mass were reduced, with single-cell RNA sequencing revealing downregulation of the Wnt pathway in osteogenic periosteal cells, which is critical for maintaining cortical bone. Transcriptomic analysis of periosteal cells from humans with T2DM further underscored the evolutionary conservation of osteogenic properties. A comprehensive atlas of periosteal cells under WT and T2DM conditions, pre- and post-fracture, identified induced fibrogenic cells as essential for fracture repair. Further analysis confirmed that induced fibrogenic cells contribute to both intramembranous and endochondral ossification. Importantly, we identified Fibrinogen-like Protein 2 (FGL2), expressed by fibro-adipogenic progenitors (FAPs) and periosteal cells, as a key factor hindering healing by suppressing periosteal proliferation through mitochondrial regulation via the mTORC1 pathway. These findings highlight the periosteal heterogeneity and dynamics involved in delayed fracture healing in T2DM. |
| format | Article |
| id | doaj-art-a1f20122f16b4adaa225a6935174ee40 |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-a1f20122f16b4adaa225a6935174ee402025-08-20T03:05:07ZengBMCCell Communication and Signaling1478-811X2025-08-0123111810.1186/s12964-025-02349-ySingle-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetesXing Ji0Jiahao Luo1Yangxun He2Xinhua Hu3Taotao Xu4Yuanlong Wang5Sijun Pan6Jiali Yao7Weiwei Hu8Ximei Wu9Department of Pharmacology, Zhejiang University School of MedicineDepartment of Pharmacology, Zhejiang University School of MedicineDepartment of Pharmacology, Zhejiang University School of MedicineDepartment of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical UniversityAnji People’s Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City UniversityAnji People’s Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City UniversityShulan International Medical College, Zhejiang Shuren UniversityDepartment of Pharmacology, Zhejiang University School of MedicineDepartment of Pharmacology, Zhejiang University School of MedicineAbstract Type 2 diabetes mellitus (T2DM) is associated with an elevated fracture risk and impaired healing, but the periosteum’s role in delayed repair remains unclear. In db/db mice, both trabecular and cortical bone mass were reduced, with single-cell RNA sequencing revealing downregulation of the Wnt pathway in osteogenic periosteal cells, which is critical for maintaining cortical bone. Transcriptomic analysis of periosteal cells from humans with T2DM further underscored the evolutionary conservation of osteogenic properties. A comprehensive atlas of periosteal cells under WT and T2DM conditions, pre- and post-fracture, identified induced fibrogenic cells as essential for fracture repair. Further analysis confirmed that induced fibrogenic cells contribute to both intramembranous and endochondral ossification. Importantly, we identified Fibrinogen-like Protein 2 (FGL2), expressed by fibro-adipogenic progenitors (FAPs) and periosteal cells, as a key factor hindering healing by suppressing periosteal proliferation through mitochondrial regulation via the mTORC1 pathway. These findings highlight the periosteal heterogeneity and dynamics involved in delayed fracture healing in T2DM.https://doi.org/10.1186/s12964-025-02349-yPeriosteumT2DMDelayed fracture healingFibrinogen-like Protein 2ScRNA-seq |
| spellingShingle | Xing Ji Jiahao Luo Yangxun He Xinhua Hu Taotao Xu Yuanlong Wang Sijun Pan Jiali Yao Weiwei Hu Ximei Wu Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes Cell Communication and Signaling Periosteum T2DM Delayed fracture healing Fibrinogen-like Protein 2 ScRNA-seq |
| title | Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes |
| title_full | Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes |
| title_fullStr | Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes |
| title_full_unstemmed | Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes |
| title_short | Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes |
| title_sort | single cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill hole model of type 2 diabetes |
| topic | Periosteum T2DM Delayed fracture healing Fibrinogen-like Protein 2 ScRNA-seq |
| url | https://doi.org/10.1186/s12964-025-02349-y |
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