Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Emergency Medicine Center, Jinhua Municipal Central Hospital, Zhejiang, China.
Bone Res. 2024 Nov 21;12(1):67. doi: 10.1038/s41413-024-00373-1.
Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(mA)-methylated modification regulates autophagy in IVDD-NPCs. Mechanistically, lysine methyltransferase 2A (KMT2A) promoted the expression of methyltransferase-like 3 (METTL3) through H3K4me3 modification, whereas METTL3-mediated mA modification reduced the expression of autophagy-associated 4a (ATG4a) by attenuating its RNA stability, leading to autophagy damage in NPCs. Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs. Therefore, targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.
椎间盘退变（IVDD）是一种与年龄相关的疾病，随着 IVDD 的进展，衰老的髓核细胞（NPC）明显增加。然而，调节 NPC 衰老的具体机制尚不清楚。在本研究中，我们观察到 IVDD-NPC 中的自噬受损，这导致 NPC 衰老和衰老相关分泌表型（SASP）的上调。失调的 SASP 破坏了 NPC 的活力，并引发细胞外基质降解。相反，自噬的恢复通过抑制 GATA 结合蛋白 4（GATA4）逆转了衰老表型。此外，我们还观察到一个新现象，即组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）修饰和 N6-甲基腺苷（m6A）甲基化修饰之间的串扰调节 IVDD-NPC 中的自噬。在机制上，赖氨酸甲基转移酶 2A（KMT2A）通过 H3K4me3 修饰促进了甲基转移酶样 3（METTL3）的表达，而 METTL3 介导的 m6A 修饰通过降低自噬相关 4a（ATG4a）的 RNA 稳定性来减少其表达，从而导致 NPC 中的自噬损伤。沉默 KMT2A 和 METTL3 增强了 IVDD-NPC 中的自噬流并抑制了 SASP 表达。因此，靶向 H3K4me3 调节的 METTL3/ATG4a/GATA4 轴可能代表 IVDD 的一种有前途的新治疗策略。
