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Here, we directly addressed this issue by first developing and validating a\n                    <jats:italic>p21<\/jats:italic>\n                    \u2010\n                    <jats:italic>ATTAC<\/jats:italic>\n                    mouse with the\n                    <jats:italic>\n                      p21\n                      <jats:sup>Cip1<\/jats:sup>\n                    <\/jats:italic>\n                    promoter driving a \u201csuicide\u201d transgene encoding an inducible caspase\u20108 which, upon induction, selectively kills p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    \u2010expressing senescent cells. Next, we used the\n                    <jats:italic>p21<\/jats:italic>\n                    \u2010\n                    <jats:italic>ATTAC<\/jats:italic>\n                    mouse and the established\n                    <jats:italic>p16<\/jats:italic>\n                    \u2010\n                    <jats:italic>INK<\/jats:italic>\n                    \u2010\n                    <jats:italic>ATTAC<\/jats:italic>\n                    mouse to directly compare the contributions of p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    versus p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    in driving cellular senescence in a condition where a tissue phenotype (bone loss and increased marrow adiposity) is clearly driven by cellular senescence\u2014specifically, radiation\u2010induced osteoporosis. Using RNA in situ hybridization, we confirmed the reduction in radiation\u2010induced\n                    <jats:italic>\n                      p21\n                      <jats:sup>Cip1<\/jats:sup>\n                    <\/jats:italic>\n                    \u2010 or\n                    <jats:italic>\n                      p16\n                      <jats:sup>Ink4a<\/jats:sup>\n                    <\/jats:italic>\n                    \u2010driven transcripts following senescent cell clearance in both models. However, only clearance of p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    +, but not p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    +, senescent cells prevented both radiation\u2010induced osteoporosis and increased marrow adiposity. Reduction in senescent cells with dysfunctional telomeres following clearance of p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    +, but not p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    +, senescent cells also reduced several of the radiation\u2010induced pro\u2010inflammatory senescence\u2010associated secretory phenotype factors. Thus, by directly comparing senescent cell clearance using two parallel genetic models, we demonstrate that radiation\u2010induced osteoporosis is driven predominantly by p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    \u2010 rather than p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    \u2010mediated cellular senescence. Further, this approach can be used to dissect the contributions of these pathways in other senescence\u2010associated conditions, including aging across tissues.\n                  <\/jats:p>","DOI":"10.1111\/acel.13602","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T14:55:00Z","timestamp":1648824900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Targeted clearance of\n                    <i>p21<\/i>\n                    \u2010 but not\n                    <i>p16<\/i>\n                    \u2010positive senescent cells prevents radiation\u2010induced osteoporosis and increased marrow adiposity"],"prefix":"10.1111","volume":"21","author":[{"given":"Abhishek","family":"Chandra","sequence":"first","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  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