Skeletal stem cell lineages in osteosarcoma and bone metastasis

Skeletal stem cells (SSCs) and their lineage derivatives play essential roles in bone development, maintenance, and regeneration. In addition to their physiological functions, SSCs have been implicated in primary bone tumor development and bone metastasis. Recent lineage-tracing studies have identified fibroblast growth factor receptor 3 (Fgfr3)-positive endosteal stem cells as a distinct SSC population residing along the endosteal surface of juvenile long bones.

This review comprehensively synthesizes previous studies on skeletal stem cells and their lineage derivatives, integrating findings from lineage-tracing approaches, genetically engineered mouse models, and bone tumor models. By organizing current knowledge of SSC hierarchy and differentiation, we provide a framework for understanding how SSC-derived lineages contribute to both bone homeostasis and cancer-related processes.

Fgfr3⁺ endosteal stem cells give rise to osteoblasts and C-X-C motif chemokine ligand 12 (Cxcl12)-positive bone marrow reticular stromal cells that organize the hematopoietic niche. In temporally controlled Fgfr3-creER; Trp53^fl/fl models, Trp53 deletion within the endosteal stem cell niche rapidly induces high-penetrance osteosarcoma, indicating that this niche is particularly vulnerable to malignant transformation. Beyond tumor initiation, SSC-derived Cxcl12-expressing stromal cells differentiate into cancer-associated fibroblasts that promote metastatic colonization, angiogenesis, and immunosuppression in bone.

Collectively, these findings highlight Fgfr3⁺ endosteal stem cells as candidate cells of origin for osteosarcoma and underscore the dual role of SSC-derived lineages in both tumor initiation and progression. Targeting SSC-derived endosteal niches may provide new therapeutic opportunities for bone malignancies.