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Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration.
Aging Cell ( IF 8.0 ) Pub Date : 2020-06-21 , DOI: 10.1111/acel.13162 Yingchao Han 1, 2, 3 , Chao-Ming Zhou 3 , Hongxing Shen 1 , Jun Tan 2 , Qing Dong 3 , Lei Zhang 4, 5 , Sara J McGowan 4 , Jing Zhao 4 , Gwendolyn A Sowa 3, 6 , James D Kang 7 , Laura J Niedernhofer 4, 5 , Paul D Robbins 4, 5 , Nam N Vo 3
Aging Cell ( IF 8.0 ) Pub Date : 2020-06-21 , DOI: 10.1111/acel.13162 Yingchao Han 1, 2, 3 , Chao-Ming Zhou 3 , Hongxing Shen 1 , Jun Tan 2 , Qing Dong 3 , Lei Zhang 4, 5 , Sara J McGowan 4 , Jing Zhao 4 , Gwendolyn A Sowa 3, 6 , James D Kang 7 , Laura J Niedernhofer 4, 5 , Paul D Robbins 4, 5 , Nam N Vo 3
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Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the human intervertebral disc, we exposed human nucleus pulposus (hNP) cells directly to the DNA damaging agent cisplatin. Cisplatin‐treated hNP cells exhibited rapid phosphorylation of ATM and subsequent increased NF‐κB activation, aggrecanolysis, decreased total proteoglycan production and increased expression of markers of senescence, including p21, γH2AX and SA‐ß‐gal. Treating cisplatin‐exposed hNP cells with an ATM‐specific inhibitor negated these effects. In addition, genetic reduction of ATM reduced disc cellular senescence and matrix proteoglycan loss in the progeroid Ercc1−/∆ mouse model of accelerated ageing. These findings suggest that activation of ATM signalling under persistent genotoxic stress promotes disc cellular senescence and matrix homeostatic perturbation. Thus, the ATM signalling pathway represents a therapeutic target to delay the progression of age‐associated spine pathologies.
中文翻译：
共济失调的毛细血管扩张突变信号减弱与年龄相关的椎间盘退变。
以前，我们报道了持续的DNA损伤会加速脊柱的衰老，但是对该过程背后的机制尚不了解。共济失调毛细血管扩张症（ATM）是一种参与DNA损伤反应的蛋白激酶，它控制着细胞命运，包括细胞死亡。为了测试ATM在人类椎间盘中的作用，我们将人类髓核（hNP）细胞直接暴露于DNA破坏剂顺铂。顺铂处理HNP细胞显示出ATM的快速磷酸化和随后增加NF-κB活化，aggrecanolysis，总蛋白聚糖生产和衰老的标志物的表达增加，包括P21，γH降低2AX和SA-ß-gal。用ATM特异性抑制剂处理顺铂暴露的hNP细胞可消除这些影响。此外，在加速衰老的早老型Ercc1 -//Δ小鼠模型中，ATM的遗传还原减少了椎间盘细胞的衰老和基质蛋白聚糖的损失。这些发现表明，在持续的遗传毒性压力下激活ATM信号会促进椎间盘细胞衰老和基质体内稳态扰动。因此，ATM信号通路代表了延缓与年龄相关的脊柱病理学进展的治疗靶标。
更新日期：2020-06-21
中文翻译：
共济失调的毛细血管扩张突变信号减弱与年龄相关的椎间盘退变。
以前，我们报道了持续的DNA损伤会加速脊柱的衰老，但是对该过程背后的机制尚不了解。共济失调毛细血管扩张症（ATM）是一种参与DNA损伤反应的蛋白激酶，它控制着细胞命运，包括细胞死亡。为了测试ATM在人类椎间盘中的作用，我们将人类髓核（hNP）细胞直接暴露于DNA破坏剂顺铂。顺铂处理HNP细胞显示出ATM的快速磷酸化和随后增加NF-κB活化，aggrecanolysis，总蛋白聚糖生产和衰老的标志物的表达增加，包括P21，γH降低2AX和SA-ß-gal。用ATM特异性抑制剂处理顺铂暴露的hNP细胞可消除这些影响。此外，在加速衰老的早老型Ercc1 -//Δ小鼠模型中，ATM的遗传还原减少了椎间盘细胞的衰老和基质蛋白聚糖的损失。这些发现表明，在持续的遗传毒性压力下激活ATM信号会促进椎间盘细胞衰老和基质体内稳态扰动。因此，ATM信号通路代表了延缓与年龄相关的脊柱病理学进展的治疗靶标。
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