ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging.
ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging.
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DOI：
10.1097/brs.0b013e31824ee8f7
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发表时间：
2012-10-01
期刊：
影响因子：
3
通讯作者：
Vo NV
中科院分区：
文献类型：
--
作者：
Nasto LA;Seo HY;Robinson AR;Tilstra JS;Clauson CL;Sowa GA;Ngo K;Dong Q;Pola E;Lee JY;Niedernhofer LJ;Kang JD;Robbins PD;Vo NV
在一个加速衰老的小鼠模型中，核因子-κB的活性在药物和遗传上被阻断，以减轻与年龄相关的椎间盘退行性变化。探讨核因子-κB信号通路在增龄性腰椎间盘退变中的调节作用。衰老是导致椎间盘退变(IDD)的主要因素，但这一过程背后的分子机制尚不清楚。核因子-κB是一个转录因子家族，在介导细胞对损伤、应激和炎症的反应中发挥核心作用。越来越多的证据表明，慢性NF-κB激活是许多衰老相关疾病的罪魁祸首，但它在衰老相关缺铁性疾病中的作用还没有得到充分的研究。我们利用先前报道的与年龄相关的缺铁性缺铁性缺失小鼠(ERCC1-/κ小鼠)的加速老化模型，研究了抑制核转录因子-DNAB对缺铁性缺铁的影响。系统地抑制核因子-κB的激活是通过基因上缺失核因子-κB亚单位p65(ERCC1-/Δp65+/-小鼠)的一个等位基因来实现的，或者通过在ERCC1-/κ小鼠体内长期给予NEMO结合结构域(8K-NBD)来阻断核因子-κB的上游激活物IΔB诱导的激酶(IKK)的形成。对处理组和未处理组小鼠的椎间盘细胞密度、总蛋白多糖含量和蛋白多糖合成进行了评估。与年轻的WT小鼠相比，早衰期ERCC1-/κ小鼠和自然衰老的野生型小鼠的椎间盘基质蛋白多糖含量降低，而椎间盘核转录因子-ΔB活性升高。在ERCC1-/κ小鼠中，8K-Δ多肽对NF-NBDB的全身性抑制增加了盘蛋白多糖的合成，增加了盘细胞和基质蛋白多糖的糖化损失。这些结果通过使用p65单倍体缺陷的ERCC1-/Δp65+/-小鼠得到了遗传学上的证实。这些发现表明，IKK/NF-κB信号通路是年龄依赖性缺乏症的关键调节因子，是减轻与衰老相关的椎间盘退行性疾病的治疗靶点。
NF-κB activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes. To study the mediatory role of NF-κB signaling pathway in age-dependent intervertebral disc degeneration. Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-κB is a family of transcription factors which play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-κB activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-κB inhibition on IDD using a DNA repair-deficient mouse model of accelerated aging (Ercc1-/Δ mice) previously been reported to exhibit age-related IDD. Systemic inhibition of NF-κB activation was achieved either genetically by deletion of one allele of the NF-κB subunit p65 (Ercc1-/Δp65+/- mice) or pharmacologically by chronic intra-peritoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-κB, IκB Inducible Kinase (IKK), in Ercc1-/Δ mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice and untreated controls were assessed. Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-κB activity were observed in discs of progeroid Ercc1-/Δ mice and naturally aged wild-type compared to young WT mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1-/Δ mice increased disc proteoglycan synthesis and ameriolated loss disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1-/Δp65+/- mice. These findings demonstrate that the IKK/NF-κB signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.