正常小鼠骨骼发育过程中的内皮细胞向成骨细胞转变

Endothelial-to-osteoblast transition in normal mouse bone development.

作者信息

Lin Song-Chang, Yu Guoyu, Lee Yu-Chen, Song Jian H, Song Xingzhi, Zhang Jianhua, Panaretakis Theocharis, Logothetis Christopher J, Komatsu Yoshihiro, Yu-Lee Li-Yuan, Wang Guocan, Lin Sue-Hwa

机构信息

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

iScience. 2023 Jan 16;26(2):105994. doi: 10.1016/j.isci.2023.105994. eCollection 2023 Feb 17.

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 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.

骨转移性前列腺癌（PCa）会引发骨形成性病变。我们之前已经表明，前列腺癌诱导形成的骨起源于经历了内皮细胞（EC）向成骨细胞（OSB）转变的内皮细胞。在此，我们研究了在正常骨形成过程中是否也会发生内皮细胞向成骨细胞的转变。我们构建了一种内皮细胞和成骨细胞双色报告基因小鼠（DRM）模型，该模型用红色和绿色荧光蛋白标记内皮细胞 - 成骨细胞杂交细胞。我们在胚胎发育和成体阶段的软骨内成骨和膜内成骨过程中均观察到了内皮细胞向成骨细胞的转变（红色荧光蛋白和绿色荧光蛋白共表达）。从DRM分离出的细胞中证实了共表达现象。骨髓和肺来源的内皮细胞在成骨培养基中会转变为成骨细胞并发生矿化。RNA测序显示，GATA家族转录因子在内皮细胞 - 成骨细胞杂交细胞中上调，而敲低会抑制骨形态发生蛋白4（BMP4）诱导的矿化。我们的研究结果支持内皮细胞向成骨细胞的转变发生在正常骨发育过程中，并提出了关于成骨细胞内皮起源的新范式。