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

## TL;DR

This study explores how diabetes affects bone healing by analyzing cell activity in the periosteum, identifying a key protein that hinders recovery.

## Contribution

The study reveals FGL2 as a novel factor impairing periosteal cell proliferation in T2DM through mitochondrial regulation.

## Key findings

- Single-cell RNA sequencing shows Wnt pathway downregulation in osteogenic periosteal cells in T2DM.
- FGL2, expressed by FAPs and periosteal cells, suppresses healing via mTORC1 pathway regulation.
- Induced fibrogenic cells are essential for fracture repair through intramembranous and endochondral ossification.

## 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.

The online version contains supplementary material available at 10.1186/s12964-025-02349-y.