TY - JOUR
T1 - Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin
AU - Velletri, Tania
AU - Huang, Yin
AU - Wang, Yu
AU - Li, Qing
AU - Hu, Mingyuan
AU - Xie, Ningxia
AU - Yang, Qian
AU - Chen, Xiaodong
AU - Chen, Qing
AU - Shou, Peishun
AU - Gan, Yurun
AU - Candi, Eleonora
AU - Margherita, Annicchiarico Petruzzelli
AU - Agostini, Massimiliano
AU - Yang, Huilin
AU - Melino, Gerry
AU - Shi, Yufang
AU - Wang, Ying
N1 - Funding Information:
Acknowledgements We sincerely thank the generous help for providing p53f/f mice and prostate cancer cell lines from Dr. Jun Qin in Shanghai Institute of Nutrition and Health. This work is supported by grants from the National Key R&D Program of China (2018YFA0107500), the Scientific Innovation Project of the Chinese Academy of Sciences (XDA16020403), the National Natural Science Foundation of China (81861138015, 31961133024, 31771641, 31601106, 81930085, and 81571612), the National Key R&D Program of China (2018YFC1704300), the MAECI Italy-China Science and Technology Cooperation (#PGR00961), the Youth Innovation Promotion Association research fund from the Chinese Academy of Sciences, the Ministry of Health Italy-China cooperation grant, and partially by the Medical Research Council, Associazione Italiana per la Ricerca contro il Cancro (AIRC, IG#20473; 2018-2022), Fondazione Luigi Maria Monti IDI-IRCCS (RC to EC), AIRC (IG#22206; 2019-2023) to EC. Work has been also supported by Regione Lazio through Lazio Innova Progetto Gruppo di Ricerca n 85-2017-14986 and by the Medical Research Council (to GM).
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41418-020-0590-4
DO - 10.1038/s41418-020-0590-4
M3 - Article
C2 - 32694652
AN - SCOPUS:85088237094
VL - 28
SP - 156
EP - 169
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 1
ER -