Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis.
Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis.
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Senolytic药物旨在选择性地清除随着损伤或衰老而积累的衰老细胞（SnC）。在骨关节炎（OA）的小鼠模型中，senolysis产生促再生反应，但在老年小鼠中的治疗益处减少。氧化应激增加是老年人的一个标志。因此，在这里，我们调查是否senolytic治疗差异影响联合氧化负荷在年轻和老年动物。我们发现，senolysis的p53/MDM 2相互作用抑制剂，UBX 0101，减少蛋白质氧化修饰在老年关节炎膝关节。质谱结合蛋白质相互作用网络分析和生物物理学稳定性预测提取的关节蛋白揭示了不同的响应年轻和老年动物之间的senolysis，广泛表明，膝关节再生和细胞应力程序是相反的准备响应作为年龄的函数。这些相反的反应包括蛋白质氧化修饰和丰度变化的不同特征，修饰蛋白质网络中心性的不同定量趋势，以及年轻人和老年人之间氧化诱导的折叠自由能扰动的对比模式。我们开发了一种复合敏感性评分，以确定老年骨关节炎关节蛋白质组中的特定关键蛋白，从而提名前瞻性治疗靶点，以补充senolytics。 通过p53/MDM 2相互作用抑制剂进行的衰老清除治疗降低了骨关节炎（OA）老年小鼠模型中的关节蛋白氧化应激负荷。蛋白质相互作用网络和生物物理稳定性分析配对的质谱蛋白质组学询问揭示了年轻和老年动物之间对senolysis的不同反应。我们开发了一种复合敏感性评分，以确定老年骨关节炎关节蛋白质组中的特定关键蛋白。
Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro‐regenerative response, but the therapeutic benefit is reduced in aged mice. Increased oxidative stress is a hallmark of advanced age. Therefore, here we investigate whether senolytic treatment differentially affects joint oxidative load in young and aged animals. We find that senolysis by a p53/MDM2 interaction inhibitor, UBX0101, reduces protein oxidative modification in the aged arthritic knee joint. Mass spectrometry coupled with protein interaction network analysis and biophysical stability prediction of extracted joint proteins revealed divergent responses to senolysis between young and aged animals, broadly suggesting that knee regeneration and cellular stress programs are contrarily poised to respond as a function of age. These opposing responses include differing signatures of protein‐by‐protein oxidative modification and abundance change, disparate quantitative trends in modified protein network centrality, and contrasting patterns of oxidation‐induced folding free energy perturbation between young and old. We develop a composite sensitivity score to identify specific key proteins in the proteomes of aged osteoarthritic joints, thereby nominating prospective therapeutic targets to complement senolytics. Senolytic treatment by a p53/MDM2 interaction inhibitor reduces joint protein oxidative stress load in an aged mouse model of osteoarthritis (OA). Mass spectrometry proteomic interrogation paired with protein interaction network and biophysical stability analysis reveals divergent responses to senolysis between young and aged animals. We develop a composite sensitivity score to identify specific key proteins in the proteomes of aged osteoarthritic joints.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
5.3
作者：
Arif, Abul;Chatterjee, Piyali;Fox, Paul L.
通讯作者：
Fox, Paul L.
影响因子：
9.3
作者：
Munier, Claire C.;Ottmann, Christian;Perry, Matthew W. D.
通讯作者：
Perry, Matthew W. D.
影响因子：
--
作者：
Lee, CR;Breinan, HA;Spector, M
通讯作者：
Spector, M