Luo Xiaoji, Chen Jin, Song Wen-Xin, Tang Ni, Luo Jinyong, Deng Zhong-Liang, Sharff Katie A, He Gary, Bi Yang, He Bai-Cheng, Bennett Erwin, Huang Jiayi, Kang Quan, Jiang Wei, Su Yuxi, Zhu Gao-Hui, Yin Hong, He Yun, Wang Yi, Souris Jeffrey S, Chen Liang, Zuo Guo-Wei, Montag Anthony G, Reid Russell R, Haydon Rex C, Luu Hue H, He Tong-Chuan
Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Department of Pediatric Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China.
Lab Invest. 2008 Dec;88(12):1264-77. doi: 10.1038/labinvest.2008.98. Epub 2008 Oct 6.
Osteosarcoma (OS) is the most common primary malignancy of bone. Here, we investigated a possible role of defective osteoblast differentiation in OS tumorigenesis. We found that basal levels of the early osteogenic marker alkaline phosphatase (ALP) activity were low in OS lines. Osteogenic regulators Runx2 and OSX, and the late marker osteopontin (OPN) expressed at low levels in most OS lines, indicating that most OS cells fail to undergo terminal differentiation. Furthermore, OS cells were refractory to osteogenic BMP-induced increases in ALP activity. Osteogenic BMPs were shown to upregulate early target genes, but not late osteogenic markers OPN and osteocalcin (OC). Furthermore, osteogenic BMPs failed to induce bone formation from human OS cells, rather effectively promoted OS tumor growth in an orthotopic OS model. Exogenous expression of early target genes enhanced BMP-stimulated OS tumor growth, whereas osteogenic BMP-promoted OS tumor growth was inhibited by exogenous Runx2 expression. These results suggest that alterations in osteoprogenitors may disrupt osteogenic differentiation pathway. Thus, identifying potential differentiation defects in OS tumors would allow us to reconstruct the tumorigenic events in osteoprogenitors and to develop rational differentiation therapies for clinical OS management.
骨肉瘤（OS）是最常见的原发性骨恶性肿瘤。在此，我们研究了成骨细胞分化缺陷在骨肉瘤发生中的可能作用。我们发现，在骨肉瘤细胞系中，早期成骨标志物碱性磷酸酶（ALP）活性的基础水平较低。成骨调节因子Runx2和OSX以及晚期标志物骨桥蛋白（OPN）在大多数骨肉瘤细胞系中表达水平较低，这表明大多数骨肉瘤细胞无法进行终末分化。此外，骨肉瘤细胞对成骨BMP诱导的ALP活性增加具有抗性。成骨BMP被证明可上调早期靶基因，但不能上调晚期成骨标志物OPN和骨钙素（OC）。此外，成骨BMP不能诱导人骨肉瘤细胞形成骨，反而在原位骨肉瘤模型中有效地促进了骨肉瘤肿瘤生长。早期靶基因的外源性表达增强了BMP刺激的骨肉瘤肿瘤生长，而成骨BMP促进的骨肉瘤肿瘤生长则被外源性Runx2表达所抑制。这些结果表明，骨祖细胞的改变可能会破坏成骨分化途径。因此，识别骨肉瘤肿瘤中潜在的分化缺陷将使我们能够重建骨祖细胞中的致瘤事件，并开发合理的分化疗法用于临床骨肉瘤治疗。
