Journal Article

Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin

Shou, Peishun, Yang, Qian, Wang, Yu, Li, Qing, Xie, Ningxia, Wang, Ying, Agostini, Massimiliano, Annicchiarico-Petruzzelli, Margherita, Velletri, Tania, Huang, Yin, Chen, Xiaodong, Shi, Yufang, Yang, Huilin, Hu, Mingyuan, Candi, Eleonora, Melino, Gerry, Chen, Qing, Gan, Yurun

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/31 / 631/80 / 64/60 / 692/420 / 96/100 / Animals / Apoptosis / Biochemistry / Biomedical and Life Sciences / Bone cancer / Bone density / Bone growth / Bone marrow / Bone Remodeling / Bone turnover / Cell Biology / Cell cycle / Cell Cycle Analysis / Cell Differentiation / Cell Line, Tumor / Computed tomography / Homeostasis / Humans / Life Sciences / Male / Mesenchymal stem cells / Mesenchymal Stem Cells - metabolism / Mice / Mice, Inbred C57BL / Mice, Nude / Microenvironments / NF-kappa B - metabolism / NF-κB protein / Osteogenesis / Osteogenesis - genetics / Osteoprogenitor cells / Osteoprotegerin / Osteoprotegerin - metabolism / Osteosarcoma / Osteosarcoma - pathology / p53 Protein / Progenitor cells / Prostate cancer / Prostatic Neoplasms - pathology / Receptor Activator of Nuclear Factor-kappa B - metabolism / Sarcoma / Signal Transduction / Stem cell transplantation / Stem Cells / TRANCE protein / Transcription Factor RelA / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism