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Title: Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice

Abstract

Both an increase in osteoclast and a decrease in osteoblast numbers contribute to skeletal aging. Markers of cellular senescence, including expression of the cyclin inhibitor p16, increase with aging in several bone cell populations. The elimination of p16-expressing cells in old mice, using the INK-ATTAC transgene, increases bone mass indicating that senescent cells contribute to skeletal aging. However, the identity of the senescent cells and the extent to which ablation of p16-expressing cells may prevent skeletal aging remain unknown. Using mice expressing the p16-3MR transgene, we examined whether elimination of p16-expressing cells between 12 and 24 months of age could preserve bone mass; and whether elimination of these cells from 20 to 26 months of age could restore bone mass. The activation of the p16-3MR transgene by ganciclovir (GCV) greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated by GCV. However, GCV did not alter p16 levels in osteocytes-the most abundant cell type in bone-and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitorsmore » and senescent cells in other tissues, as described previously. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.« less

Authors:
ORCiD logo [1];  [2];  [3];  [1];  [4];  [5];  [6];  [5]
  1. Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences Little Rock Arkansas, The Central Arkansas Veterans Healthcare System Little Rock Arkansas
  2. Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute University of Arkansas for Medical Sciences Little Rock Arkansas
  3. Department of Orthopedic Surgery University of Arkansas for Medical Sciences Little Rock Arkansas
  4. Buck Institute for Research on Aging Novato California, Lawrence Berkeley National Laboratory Berkeley California
  5. Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences Little Rock Arkansas, The Central Arkansas Veterans Healthcare System Little Rock Arkansas, Department of Orthopedic Surgery University of Arkansas for Medical Sciences Little Rock Arkansas
  6. Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute University of Arkansas for Medical Sciences Little Rock Arkansas, Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Electricity (OE), Advanced Grid Research & Development. Power Systems Engineering Research; National Institutes of Health (NIH); University of Arkansas for Medical Sciences Tobacco Funds and Translational Research Institute; US Department of Veterans Affairs
OSTI Identifier:
1494949
Alternate Identifier(s):
OSTI ID: 1494950; OSTI ID: 1559223
Grant/Contract Number:  
AC02-05CH11231; 1UL1RR029884; P20GM125503; R01 AR56679 R01 CA122023; R01 CA211963
Resource Type:
Published Article
Journal Name:
Aging Cell
Additional Journal Information:
Journal Name: Aging Cell Journal Volume: 18 Journal Issue: 3; Journal ID: ISSN 1474-9718
Publisher:
Wiley-Blackwell
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; aging; osteoblasts; osteocytes; osteoporosis

Citation Formats

Kim, Ha‐Neui, Chang, Jianhui, Iyer, Srividhya, Han, Li, Campisi, Judith, Manolagas, Stavros C., Zhou, Daohong, and Almeida, Maria. Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice. United States: N. p., 2019. Web. doi:10.1111/acel.12923.
Kim, Ha‐Neui, Chang, Jianhui, Iyer, Srividhya, Han, Li, Campisi, Judith, Manolagas, Stavros C., Zhou, Daohong, & Almeida, Maria. Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice. United States. doi:10.1111/acel.12923.
Kim, Ha‐Neui, Chang, Jianhui, Iyer, Srividhya, Han, Li, Campisi, Judith, Manolagas, Stavros C., Zhou, Daohong, and Almeida, Maria. Sun . "Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice". United States. doi:10.1111/acel.12923.
@article{osti_1494949,
title = {Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice},
author = {Kim, Ha‐Neui and Chang, Jianhui and Iyer, Srividhya and Han, Li and Campisi, Judith and Manolagas, Stavros C. and Zhou, Daohong and Almeida, Maria},
abstractNote = {Both an increase in osteoclast and a decrease in osteoblast numbers contribute to skeletal aging. Markers of cellular senescence, including expression of the cyclin inhibitor p16, increase with aging in several bone cell populations. The elimination of p16-expressing cells in old mice, using the INK-ATTAC transgene, increases bone mass indicating that senescent cells contribute to skeletal aging. However, the identity of the senescent cells and the extent to which ablation of p16-expressing cells may prevent skeletal aging remain unknown. Using mice expressing the p16-3MR transgene, we examined whether elimination of p16-expressing cells between 12 and 24 months of age could preserve bone mass; and whether elimination of these cells from 20 to 26 months of age could restore bone mass. The activation of the p16-3MR transgene by ganciclovir (GCV) greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated by GCV. However, GCV did not alter p16 levels in osteocytes-the most abundant cell type in bone-and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitors and senescent cells in other tissues, as described previously. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.},
doi = {10.1111/acel.12923},
journal = {Aging Cell},
number = 3,
volume = 18,
place = {United States},
year = {2019},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1111/acel.12923

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Cited by: 3 works
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