Ji Xing, Luo Jiahao, He Yangxun, Hu Xinhua, Xu Taotao, Wang Yuanlong, Pan Sijun, Yao Jiali, Hu Weiwei, Wu Ximei
Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
Department of Pharmacology, Hangzhou City University School of Medicine, 51 Huzhou Street, Hangzhou, 310015, China.
Cell Commun Signal. 2025 Aug 12;23(1):371. doi: 10.1186/s12964-025-02349-y.
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.
2型糖尿病（T2DM）与骨折风险升高及愈合受损相关，但骨膜在延迟修复中的作用仍不清楚。在db/db小鼠中，小梁骨和皮质骨量均减少，单细胞RNA测序显示成骨骨膜细胞中Wnt通路下调，而Wnt通路对维持皮质骨至关重要。对T2DM患者骨膜细胞的转录组分析进一步强调了成骨特性的进化保守性。一份关于野生型和T2DM条件下骨折前后骨膜细胞的综合图谱，确定诱导性纤维生成细胞是骨折修复所必需的。进一步分析证实，诱导性纤维生成细胞有助于膜内成骨和软骨内成骨。重要的是，我们确定了由纤维脂肪生成祖细胞（FAPs）和骨膜细胞表达的纤维蛋白原样蛋白2（FGL2）是通过mTORC1通路调节线粒体来抑制骨膜增殖从而阻碍愈合的关键因素。这些发现突出了T2DM延迟骨折愈合中涉及的骨膜异质性和动态变化。
