@article{d537343d9b8541b29bb0a7200f29bbd0,
title = "Programmed cell senescence in skeleton during late puberty",
abstract = "Mesenchymal stem/progenitor cells (MSPCs) undergo rapid self-renewal and differentiation, contributing to fast skeletal growth during childhood and puberty. It remains unclear whether these cells change their properties during late puberty to young adulthood, when bone growth and accrual decelerate. Here we show that MSPCs in primary spongiosa of long bone in mice at late puberty undergo normal programmed senescence, characterized by loss of nestin expression. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3, and deletion of Ezh2 in early pubertal mice results in premature cellular senescence, depleted MSPCs pool, and impaired osteogenesis as well as osteoporosis in later life. Our data reveals a programmed cell fate change in postnatal skeleton and unravels a regulatory mechanism underlying this phenomenon.",
author = "Changjun Li and Yu Chai and Lei Wang and Bo Gao and Hao Chen and Peisong Gao and Zhou, {Feng Quan} and Xianghang Luo and Crane, {Janet L.} and Bin Yu and Xu Cao and Mei Wan",
note = "Funding Information: Here we report that MSPCs in the primary spongiosa of long bones undergo cellular senescence during late puberty when the speed of bone growth/accrual starts to slow. The senescence process is programed by a conserved mechanism because it restricts in a particular region of long bone and follows a specific time course. Cellular senescence was defined by the presence of a senescence marker SA-βGal and a key senescence mediator p16INK4a detected in the bone tissue sections. Cell senescence was also supported by a reduced proliferation rate, as detected by BrdU labeling and the expression of proliferation marker Ki67. Metaphyses, especially the primary spongiosa that lies immediately adjacent to the growth plate, are the zone of active neoan-giogenesis and osteogenesis during the rapid postnatal and pubertal skeletal growth periods. During long bone growth, the whole metaphysis is modeled. We found that cell senescence was barely detectable during early puberty, became obvious during late puberty, and was much reduced in adulthood in the primary spongiosa of mouse femora. There were many fewer senescent cells in the secondary spongiosa relative to the primary spongiosa, and senescent cells were almost undetectable in the diaphysis in the center bone marrow area, indicating that the cellular senescence may represent the primary spongiosa involuting during the late puberty. We also found that the senescence of the cells was reduced in mice treated with bone anabolic agents GH and iPTH but accelerated in mice treated with prednisolone, indicating that the progression of this process can be manipulated by external factors known to affect skeletal growth and bone accrual. Cellular senescence in primary spongiosa is an important signature for the transition from fast to slow growing phase in long bones. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41467-017-01509-0",
language = "English (US)",
volume = "8",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}