Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, 210009, Nanjing, China.
Department of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530000, China.
Nat Commun. 2018 Nov 28;9(1):5051. doi: 10.1038/s41467-018-07360-1.
Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). Here we present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. Gain- and loss-of-function studies show that miR-141 drives IDD by inducing nucleus pulposus (NP) apoptosis. Furthermore, miR-141 KO in mice attenuated spontaneous and surgically induced IDD. Mechanistically, miR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-κB pathway. Therapeutically, upregulation or downregulation of miR-141 by nanoparticle delivery in IDD model aggravated or alleviated experimental IDD, respectively. Our findings reveal a novel mechanism by which miR-141, in part, promotes IDD progression by interacting with SIRT1/NF-κB pathway. Blockade of miR-141 in vivo may serve as a potential therapeutic approach in the treatment of IDD.
了解调节椎间盘维持和破坏的分子机制可能会导致开发新的椎间盘退行性变（IDD）治疗方法。在这里，我们通过 miRNA 微阵列分析临床数据集以及体外和体内实验提供了证据，表明 miR-141 是 IDD 的关键调节因子。增益和功能丧失研究表明，miR-141 通过诱导髓核（NP）细胞凋亡来驱动 IDD。此外，miR-141 在小鼠中的 KO 减轻了自发性和手术诱导的 IDD。从机制上讲，miR-141 通过靶向和耗尽 NF-κB 通路的负调节因子 SIRT1 来促进 IDD 的发展。在治疗方面，在 IDD 模型中通过纳米颗粒递送上调或下调 miR-141 分别加重或减轻了实验性 IDD。我们的研究结果揭示了一种新的机制，即 miR-141 通过与 SIRT1/NF-κB 通路相互作用，在一定程度上促进了 IDD 的进展。体内阻断 miR-141 可能成为治疗 IDD 的一种潜在治疗方法。
