Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
复制标题
DOI：
10.1002/jbmr.3978
复制
发表时间：
2020-06-01
影响因子：
6.2
通讯作者：
Pignolo, Robert J.
中科院分区：
文献类型：
--
作者：
Chandra, Abhishek;Lagnado, Anthony B.;Pignolo, Robert J.
临床放疗治疗危及生命的癌症，但辐射经常影响邻近的正常组织，包括骨。电离辐射的急性效应包括氧化应激、DNA损伤和细胞凋亡。我们在这项研究中表明，很大比例的骨髓细胞、成骨细胞和基质嵌入的骨细胞从这些损伤中恢复过来，只是达到衰老的特征。C57BL/6雄性小鼠在局灶放射治疗（FRT）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）活性和端粒功能障碍诱导病灶（TIF）的骨骼分析证实了衰老细胞的发育和衰老相关分泌表型（SASP）。衰老细胞和SASP标记物的积累与frt后42天骨结构的显著减少相关。为了测试清除衰老细胞的抗衰老药物是否能减轻frt相关的骨损伤，我们使用了抗衰老药物达沙替尼(D)、槲皮素(Q)、非瑟酮(F)和D和Q的混合物（D+Q）。我们发现D和Q作为单独的化合物可以适度减轻辐射引起的骨损伤，但f则没有这种改善。然而，通过TIF（+）成骨细胞和骨细胞、衰老标志物（p16（Ink4a）和p21）以及关键的SASP因子评估，D+Q的抗衰老混合物减少了衰老细胞负担，导致辐射股骨的骨结构显著恢复。总之，本研究提供了衰老细胞在放疗相关骨损伤中发挥作用的概念的证据，并且通过衰老剂减少衰老细胞负担是减轻放疗相关骨恶化的潜在治疗选择。(c) 2020年美国骨与矿物研究学会。
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-beta-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)andp21), 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. (c) 2020 American Society for Bone and Mineral Research.