Endothelial-to-osteoblast transition in normal mouse bone development

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and mineralization in osteogenic medium. RNA-sequencing revealed GATA family transcription factors were upregulated in EC-OSB hybrid cells and knockdown of GATA3 inhibited BMP4-induced mineralization. Our findings support that EC-to-OSB transition occurs during normal bone development and suggest a new paradigm regarding the endothelial origin of OSBs. [Display omitted] •A lineage-tracing mouse model reveals EC-to-OSB transition in normal bone formation•In vivo, cells on bone surface showed both EC (RFP) and OSB (GFP) fluorescence•In vitro, bone marrow– or lung-derived ECs transitioned to OSB and mineralized•RNAseq showed GATA3 transcription factor is involved in EC-to-OSB transition Biological sciences; Cell biology; Cancer