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Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-07-21 , DOI: 10.1038/s41418-020-0590-4
Tania Velletri 1, 2 , Yin Huang 1 , Yu Wang 1 , Qing Li 1 , Mingyuan Hu 1 , Ningxia Xie 3, 4 , Qian Yang 1 , Xiaodong Chen 1 , Qing Chen 1 , Peishun Shou 1 , Yurun Gan 1 , Eleonora Candi 3, 5 , Margherita Annicchiarico-Petruzzelli 5 , Massimiliano Agostini 3 , Huilin Yang 6 , Gerry Melino 3, 7 , Yufang Shi 1, 3, 6 , Ying Wang 1
Affiliation  

p53 plays a pivotal role in controlling the differentiation of mesenchymal stem cells (MSCs) by regulating genes involved in cell cycle and early steps of differentiation process. In the context of osteogenic differentiation of MSCs and bone homeostasis, the osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB (OPG/RANKL/RANK) axis is a critical signaling pathway. The absence or loss of function of p53 has been implicated in aberrant osteogenic differentiation of MSCs that results in higher bone formation versus erosion, leading to an unbalanced bone remodeling. Here, we show by microCT that mice with p53 deletion systemically or specifically in mesenchymal cells possess significantly higher bone density than their respective littermate controls. There is a negative correlation between p53 and OPG both in vivo by analysis of serum from p53+/+, p53+/−, and p53−/− mice and in vitro by p53 knockdown and ChIP assay in MSCs. Notably, high expression of Opg or its combination with low level of p53 are prominent features in clinical cancer lesion of osteosarcoma and prostate cancer respectively, which correlate with poor survival. Intra-bone marrow injection of prostate cancer cells, together with androgen can suppress p53 expression and enhance local Opg expression, leading to an enhancement of bone density. Our results support the notion that MSCs, as osteoblast progenitor cells and one major component of bone microenvironment, represent a cellular source of OPG, whose amount is regulated by the p53 status. It also highlights a key role for the p53-OPG axis in regulating the cancer associated bone remodeling.



中文翻译:

间充质干细胞中 p53 的缺失通过骨保护素的负调节促进骨重塑的改变。

p53 通过调节参与细胞周期和分化过程早期步骤的基因,在控制间充质干细胞 (MSC) 的分化方面发挥着关键作用。在MSCs的成骨分化和骨稳态的背景下,NF-κB配体的骨保护素/受体激活剂/NF-κB的受体激活剂(OPG/RANKL/RANK)轴是一个关键的信号通路。p53 功能的缺失或丧失与 MSC 的异常成骨分化有关,导致更高的骨形成与侵蚀,导致不平衡的骨重塑。在这里,我们通过 microCT 显示,在间充质细胞中系统性或特异性地缺失 p53 的小鼠比其各自的同窝对照小鼠具有显着更高的骨密度。+/+、p53 +/-和 p53 -/-小鼠以及体外通过 MSC 中的 p53 敲低和 ChIP 测定。值得注意的是,Opg 的高表达或其结合低水平的 p53 分别是骨肉瘤和前列腺癌临床癌症病变的突出特征,这与较差的生存相关。前列腺癌细胞骨髓内注射,与雄激素一起可抑制p53表达并增强局部Opg表达,导致骨密度增加。我们的结果支持这样的观点,即 MSC 作为成骨细胞祖细胞和骨微环境的一个主要组成部分,代表 OPG 的细胞来源,其数量受 p53 状态调节。它还强调了 p53-OPG 轴在调节癌症相关骨重塑中的关键作用。

更新日期:2020-07-21
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