Identification of Senescent Cells in the Bone Microenvironment

ABSTRACT Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA....

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Published in:Journal of bone and mineral research 2016-11, Vol.31 (11), p.1920-1929
Main Authors: Farr, Joshua N, Fraser, Daniel G, Wang, Haitao, Jaehn, Katharina, Ogrodnik, Mikolaj B, Weivoda, Megan M, Drake, Matthew T, Tchkonia, Tamara, LeBrasseur, Nathan K, Kirkland, James L, Bonewald, Lynda F, Pignolo, Robert J, Monroe, David G, Khosla, Sundeep
Format: Article
Language:English
Subjects:
AGING
ANIMAL MODELS
Animals
Biomarkers - metabolism
Bone and Bones - cytology
Cell Lineage
CELL/TISSUE SIGNALING
Cells, Cultured
Cellular Microenvironment
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
DNA, Satellite - metabolism
Female
Male
Mice, Inbred C57BL
Myeloid Cells - metabolism
Osteoblasts - cytology
Osteoblasts - metabolism
OSTEOCYTES
Osteocytes - metabolism
Phenotype
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Summary:ABSTRACT Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence‐associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age‐related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by real‐time quantitative polymerase chain reaction (rt‐qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence‐associated distension of satellites (SADS), ie, large‐scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p 
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.2892