Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Pharmacol Res. 2022 Dec;186:106537. doi: 10.1016/j.phrs.2022.106537. Epub 2022 Nov 2.
The intervertebral disc has an intrinsic circadian rhythm, elimination of which leads to stress in nucleus pulposus cells (NPCs), contributing to intervertebral disc degeneration (IDD). Disruption or deletion of Bmal1 (a core transcription factor) results in complete loss of circadian rhythms, make mice susceptibility to IDD. However, the underlying mechanism by which Bmal1 mediates IDD is remains enigmatic, and whether there are other upstream factors regulating Bmal1 in NPCs. In our study, we first found that the decrease of Bmal1 was significantly correlated with the grades of IDD. With gain- and loss-of-function, Bmal1 shown a protective effect on NPC viability and functions. Transcriptomic and proteomic landscape reveals the functional contributions of Bmal1, and phosphoproteomic analysis links to autophagy. Bioinformatics analysis identified that a novel miRNA hsa-let-7f-1-3p was directly target Bmal1 3'UTR and negatively correlated with NPC function. Finally, our animal model confirmed the protective role of Bmal1 in rat IDD and this effect could be attenuated by hsa-let-7f-1-3p. The hsa-let-7f-1-3p/Bmal1/autophagy axis provides a potential therapeutic strategy for the clinical treatment of IDD.
椎间盘具有内在的生物钟节律，消除这种节律会导致髓核细胞（NPC）的压力，导致椎间盘退变（IDD）。Bmal1（核心转录因子）的破坏或缺失会导致昼夜节律完全丧失，使小鼠易患 IDD。然而，Bmal1 介导 IDD 的潜在机制仍然是个谜，并且 NPC 中是否存在其他上游因子来调节 Bmal1。在我们的研究中，我们首先发现 Bmal1 的减少与 IDD 的严重程度显著相关。通过增益和失能实验，Bmal1 对 NPC 活力和功能表现出保护作用。转录组和蛋白质组学图谱揭示了 Bmal1 的功能贡献，磷酸蛋白质组学分析与自噬有关。生物信息学分析确定了一个新的 miRNA hsa-let-7f-1-3p 可以直接靶向 Bmal1 的 3'UTR，并与 NPC 功能呈负相关。最后，我们的动物模型证实了 Bmal1 在大鼠 IDD 中的保护作用，而 hsa-let-7f-1-3p 可以减弱这种作用。hsa-let-7f-1-3p/Bmal1/自噬轴为 IDD 的临床治疗提供了一种潜在的治疗策略。
