Fgf18 marks reserve skeletal progenitors in the fibrous periosteum contributing to bone fracture repair

The periosteum, a thin membranous tissue covering the external bone surface, is a well-established source of osteogenic activity during bone growth and fracture repair. However, the molecular identity and anatomical niche of its progenitor cells remain incompletely defined. Using single-cell RNA sequencing and RNA in situ hybridization in mouse long bones, we identified that fibroblast growth factor 18 ( Fgf18 ) expression marks a discrete subset of cells within the fibrous layer of the periosteum that co-express genes associated with skeletal stem and progenitor populations. Lineage tracing revealed that Fgf18 + cells contribute minimally to cortical bone formation under homeostatic conditions but robustly expand and generate chondrocytes and osteoblasts following injury. Targeted ablation of Fgf18 -lineage cells impaired fracture healing, confirming their functional importance. Together, these findings define Fgf18 + fibrous periosteal cells as a reserve progenitor population that is activated by injury to regenerate bone.