Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-kappaB Pathway.
Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-kappaB Pathway.
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DOI：
10.1155/2020/8319516
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发表时间：
2020-01-01
影响因子：
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通讯作者：
Chang, Cuicui
中科院分区：
文献类型：
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作者：
Bi, Fangfang;Liu, Wenbo;Chang, Cuicui
抗衰老蛋白Klotho表现出令人印象深刻的抗炎症特性，但在椎间盘损伤后早期下降，使Klotho修复成为治疗椎间盘炎症性疾病的一种有吸引力的策略。在这里，我们发现Klotho在髓核（NP）细胞中富集，Klotho的过表达主要通过抑制toll样受体4 （TLR4）来减轻h2o2诱导的急性炎症。在NP细胞（H2O2处理）和大鼠椎间盘（针刺处理）中，促炎NF-kappaB信号和细胞因子的表达与Klotho抑制和TLR4升高平行。TLR4过表达可下调Klotho的表达，而干扰TLR4表达可减弱H2O2对NP细胞Klotho的抑制作用。一致地，在椎间盘退变（IDD）模型中，RNA干扰的Klotho敲低在很大程度上降低了抗炎和椎间盘保护作用。因此，我们的研究表明，TLR4-NF-kappaB信号和Klotho在NP细胞中形成了一个负反馈回路。此外，我们还证明了Klotho的表达受TLR4-NF-kappaB信号的上调和下调之间的平衡调节。
Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-kappaB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-kappaB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-kappaB signaling.