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Bone marrow adiposity in models of radiation- and aging-related bone loss is dependent on cellular senescence
J Bone Miner Res. 2022 Mar 5. doi: 10.1002/jbmr.4537.
Abhishek Chandra 1 2 3, Anthony B Lagnado 1 3, Joshua N Farr 1 3 4, Megan Schleusner 3, David G Monroe 3 4, Dominik Saul 3 4, João F Passos 1 2 3, Sundeep Khosla 3 4, Robert J Pignolo 1 2 3 4
Abstract:
...Here we show by RNA-Sequencing data that [bone marrow adipocyte tissue, "BMAT"]-related genes were the most upregulated gene subset in radiated bones of C57BL/6 mice. Using focal radiation as a model to understand age-associated changes in bone, we performed a longitudinal assessment of cellular senescence and BMAT. Using qRT-PCR, RNA in situ hybridization of p21 transcripts and histological assessment of telomere dysfunction as a marker of senescence, we observed an increase in senescent cell burden of bone cells from day 1 post-radiation, without the presence of BMAT. BMAT was significantly elevated in radiated bones at day 7, confirming the qRT-PCR data in which most BMAT-related genes were elevated by day 7, and the trend continued until day 42 post-radiation. Similarly, elevation in BMAT-related genes was observed in bones of aged mice. The senolytic cocktail of Dasatinib (D) plus Quercetin (Q) - D+Q, which clears senescent cells, reduced BMAT in aged and radiated bones. MicroRNAs (miRs) linked with senescence marker p21 were downregulated in radiated- and aged- bones, while miR-27a, a miR that is associated with increased BMAT, was elevated both in radiated- and aged-bones. D+Q downregulated miR-27a in radiated bones at 42 days post-radiation. Overall, our study provides evidence that BMAT occurrence in oxidatively stressed bone environments, such as radiation and aging, is induced following a common pathway and is dependent on the presence of senescent cells.