Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity

Abhishek Chandra, Anthony B. Lagnado, Joshua N. Farr, Madison Doolittle, Tamara Tchkonia, James L. Kirkland, Nathan K. LeBrasseur, Paul D. Robbins, Laura J. Niedernhofer, Yuji Ikeno, João F. Passos, David G. Monroe, Robert J. Pignolo, Sundeep Khosla

Research output: Contribution to journalArticlepeer-review


Cellular senescence, which is a major cause of tissue dysfunction with aging and multiple other conditions, is known to be triggered by p16Ink4a or p21Cip1, but the relative contributions of each pathway toward inducing senescence are unclear. Here, we directly addressed this issue by first developing and validating a p21-ATTAC mouse with the p21Cip1 promoter driving a “suicide” transgene encoding an inducible caspase-8 which, upon induction, selectively kills p21Cip1-expressing senescent cells. Next, we used the p21-ATTAC mouse and the established p16-INK-ATTAC mouse to directly compare the contributions of p21Cip1 versus p16Ink4a in driving cellular senescence in a condition where a tissue phenotype (bone loss and increased marrow adiposity) is clearly driven by cellular senescence—specifically, radiation-induced osteoporosis. Using RNA in situ hybridization, we confirmed the reduction in radiation-induced p21Cip1- or p16Ink4a-driven transcripts following senescent cell clearance in both models. However, only clearance of p21Cip1+, but not p16Ink4a+, senescent cells prevented both radiation-induced osteoporosis and increased marrow adiposity. Reduction in senescent cells with dysfunctional telomeres following clearance of p21Cip1+, but not p16Ink4a+, senescent cells also reduced several of the radiation-induced pro-inflammatory senescence-associated secretory phenotype factors. Thus, by directly comparing senescent cell clearance using two parallel genetic models, we demonstrate that radiation-induced osteoporosis is driven predominantly by p21Cip1- rather than p16Ink4a-mediated cellular senescence. Further, this approach can be used to dissect the contributions of these pathways in other senescence-associated conditions, including aging across tissues.

Original languageEnglish (US)
Article numbere13602
JournalAging cell
Issue number5
StatePublished - May 2022

Bibliographical note

Funding Information:
This work was made possible by the Eagle’s Cancer Research Fund (to AC), Mayo Clinic Clinical and Translational Science Award (CTSA), grant number UL1TR002377, from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH) (to AC) and UL1TR000135, Center for Clinical and Translation Science (CCATS)(to AC), as well as the Robert and Arlene Kogod Professorship (to RJP); P01 AG062413 (SK, JNF, RJP, JLK, and TT), R01 AG063707 (DGM), R01 R01AG068048 (JFP), 1UG3CA26810‐01 (JFP), R01AG063543 (LJN), U19AG056278 (PDR/ LJN), and R01 DK128552 (JNF), and K01 AR070241 (JNF). We would like to thank Christine Hachfeld and Claire Wilhelm for their technical help with animal radiations.

Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.


  • bone
  • radiation
  • senescence

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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