Clinical radiotherapy treats life‐threatening cancers, but the radiation often affects neighboring normal tissues including bone. Acute effects of ionizing radiation include oxidative stress, DNA damage, and cellular apoptosis. We show in this study that a large proportion of bone marrow cells, osteoblasts, and matrix‐embedded osteocytes recover from these insults only to attain a senescent profile. Bone analyses of senescence‐associated genes, senescence‐associated beta‐galactosidase (SA‐β‐gal) activity, and presence of telomere dysfunction‐induced foci (TIF) at 1, 7, 14, 21, and 42 days post–focal radiation treatment (FRT) in C57BL/6 male mice confirmed the development of senescent cells and the senescence‐associated secretory phenotype (SASP). Accumulation of senescent cells and SASP markers were correlated with a significant reduction in bone architecture at 42 days post‐FRT. To test if senolytic drugs, which clear senescent cells, alleviate FRT‐related bone damage, we administered the senolytic agents, dasatinib (D), quercetin (Q), fisetin (F), and a cocktail of D and Q (D+Q). We found moderate alleviation of radiation‐induced bone damage with D and Q as stand‐alone compounds, but no such improvement was seen with F. However, the senolytic cocktail of D+Q reduced senescent cell burden as assessed by TIF⁺ osteoblasts and osteocytes, markers of senescence (p16 ^Ink4a and p21 ), and key SASP factors, resulting in significant recovery in the bone architecture of radiated femurs. In summary, this study provides proof of concept that senescent cells play a role in radiotherapy‐associated bone damage, and that reduction in senescent cell burden by senolytic agents is a potential therapeutic option for alleviating radiotherapy‐related bone deterioration. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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有针对性地减少衰老细胞负担可减轻与放疗相关的骨丢失。

临床放射疗法可治疗威胁生命的癌症，但放射线通常会影响包括骨骼在内的周围正常组织。电离辐射的急性影响包括氧化应激，DNA损伤和细胞凋亡。我们在这项研究中表明，从这些损伤中恢复了很大比例的骨髓细胞，成骨细胞和基质包埋的骨细胞，只是达到了衰老的目的。聚焦放射后1、7、14、21和42天，对衰老相关基因，衰老相关β-半乳糖苷酶（SA-β-gal）活性以及端粒功能障碍致病灶（TIF）进行骨分析C57BL / 6雄性小鼠的FRT治疗（FRT）证实了衰老细胞的发育以及与衰老相关的分泌表型（SASP）。FRT后42天，衰老细胞和SASP标记的积累与骨骼结构的显着减少有关。为了测试能清除衰老细胞的缓溶药物是否能缓解FRT相关的骨损伤，我们施用了缓溶药物达沙替尼（D），槲皮素（Q），非瑟定（F）以及D和Q的混合物（D + Q ）。我们发现以D和Q作为独立化合物可以适度减轻放射线引起的骨损伤，但是使用F则没有看到这种改善。但是，TIF评估了D + Q的骨质溶解降低了衰老细胞的负担。⁺成骨细胞和骨细胞，衰老标记（p16 ^Ink4a和p21）以及关键的SASP因子，导致放射股骨的骨结构显着恢复。总而言之，这项研究提供了概念证明，即衰老细胞在与放射治疗相关的骨损伤中起作用，并且通过缓和剂减少衰老细胞的负担是减轻与放射治疗相关的骨质恶化的潜在治疗选择。©2020美国骨骼和矿物质研究学会。