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Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity
Aging Cell. 2022 Apr 1;e13602. doi: 10.1111/acel.13602.
Abhishek Chandra 1 2, Anthony B Lagnado 1 2, Joshua N Farr 1 2 3, Madison Doolittle 2 3, Tamara Tchkonia 1 2, James L Kirkland 1 2, Nathan K LeBrasseur 2 4, Paul D Robbins 5, Laura J Niedernhofer 5, Yuji Ikeno 6, João F Passos 1 2, David G Monroe 2 3, Robert J Pignolo 1 2 3, Sundeep Khosla 1 2 3
Abstract:
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...
PMID: 35363946
Free Full-Text: https://onlinelibrary.wiley.com/doi/10.1111/acel.13602