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

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.