Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Oxid Med Cell Longev. 2017;2017:7426458. doi: 10.1155/2017/7426458. Epub 2017 Sep 24.
Senescence is a crucial driver of intervertebral disc degeneration (IDD). Disc cells are exposed to high oxygen tension due to neovascularization in degenerative discs. However, the effect of oxygen tension on disc cell senescence was unknown. Herein, rat nucleus pulposus (NP) cells were cultured under 20% O or 1% O. Consequently, ROS induced by 20% O caused DNA damage and then activated p53-p21-Rb and p16-Rb pathways via ERK signaling to induce NP cell senescence. It also induced catabolic and proinflammatory phenotype of NP cells via MAPK and NF-B pathways. Furthermore, 20% O was found to upregulate Nox4 in NP cells. Small interfering RNA against Nox4 reduced ROS production induced by 20% O and consequently suppressed premature senescence of NP cells. On the contrary, NP cells overexpressing Nox4 produced more ROS and rapidly developed senescent signs. In consistent with the in vitro studies, the expression of Nox4, p21, and Rb was upregulated in rat degenerative discs. This study, for the first time, demonstrates that Nox4 is an oxygen-sensing enzyme and a main ROS source in NP cells. Nox4-dependent ROS are genotoxic and a potent trigger of NP cell senescence. Nox4 is a potential therapeutic target for disc cell senescence and IDD.
衰老（Senescence）是椎间盘退变（IDD）的关键驱动因素。由于退变椎间盘的新生血管化（neovascularization），椎间盘细胞暴露于高氧张力（high oxygen tension）下。然而，氧张力对椎间盘细胞衰老的影响尚不清楚。在此，我们将大鼠髓核（NP）细胞在 20%氧或 1%氧中培养。结果发现，20%氧诱导的 ROS 导致 DNA 损伤，然后通过 ERK 信号激活 p53-p21-Rb 和 p16-Rb 通路，诱导 NP 细胞衰老。ROS 还通过 MAPK 和 NF-B 通路诱导 NP 细胞的分解代谢和促炎表型。此外，我们发现 20%氧上调 NP 细胞中的 Nox4。针对 Nox4 的小干扰 RNA 减少了 20%氧诱导的 ROS 产生，从而抑制了 NP 细胞的过早衰老。相反，过表达 Nox4 的 NP 细胞产生了更多的 ROS，并迅速出现衰老迹象。与体外研究一致，在大鼠退变椎间盘中，Nox4、p21 和 Rb 的表达上调。这项研究首次证明，Nox4 是 NP 细胞中的一种氧感应酶和主要 ROS 来源。Nox4 依赖性 ROS 具有遗传毒性，是 NP 细胞衰老的有力触发因素。Nox4 是治疗椎间盘细胞衰老和 IDD 的潜在靶点。
