2. Academic Validation
  3. Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes

Single-cell profiling reveals periosteal signatures of impaired periosteal cells proliferation in a drill-hole model of type 2 diabetes

  • Cell Commun Signal. 2025 Aug 12;23(1):371. doi: 10.1186/s12964-025-02349-y.
Xing Ji # 1 2,  Jiahao Luo # 1,  Yangxun He 1,  Xinhua Hu 3,  Taotao Xu 4,  Yuanlong Wang 5,  Sijun Pan 5,  Jiali Yao 6,  Weiwei Hu # 7,  Ximei Wu # 8 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
  • 2 Department of Pharmacology, Hangzhou City University School of Medicine, 51 Huzhou Street, Hangzhou, 310015, China.
  • 3 Department of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.
  • 4 Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, 310006, China.
  • 5 Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
  • 6 Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, China.
  • 7 Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China. huww@zju.edu.cn.
  • 8 Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China. xiwu@zju.edu.cn.
  • 9 Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, China. xiwu@zju.edu.cn.
  • # Contributed equally.
PMID: 40796869 DOI: 10.1186/s12964-025-02349-y
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.

Keywords

Delayed fracture healing; Fibrinogen-like Protein 2; Periosteum; ScRNA-seq; T2DM.

Figures
Products