A Subset of Osteosarcoma Bears Markers of CXCL12‐Abundant Reticular Cells

Currently, the cell of origin for osteosarcoma or other primary skeletal tumors is largely unknown. Recent reports identifying specific cell types comprising bone now newly enable investigation of this topic. Specifically, CXC motif chemokine 12 (CXCL12)‐abundant reticular (CAR) cells are a specific skeletal stromal cell type that orchestrate the bone marrow microenvironment through cross‐talk with hematopoietic and endothelial cells and a likely candidate cell of origin for at least a subset of primary skeletal tumors. Here, we analyze osteosarcomas via immunohistochemistry for known markers of CAR cells such as leptin receptor (LEPR), B‐cell factor 3 (EBF3), CXCL12, and platelet‐derived growth factor receptor alpha (PDGFRA). A large proportion of high‐grade tumors expressed LEPR, PDGFRA, and EBF3 but not CXCL12. These data raise the hypothesis that CAR cells are the cell of origin of this osteoblastic osteosarcoma subset, a finding with implications for the cellular oncogenesis of primary osteosarcoma and the development of effective targeted therapies. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.