Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Department of Orthopedics, The Sixth Affliated Hospital of Xinjiang Medical University, Urumchi 830002, China.
Biomed Pharmacother. 2019 May;113:108652. doi: 10.1016/j.biopha.2019.108652. Epub 2019 Mar 8.
Emerging evidence suggests that microRNAs (miRNAs, miRs) play important roles in the development of intervertebral disc degeneration (IVDD). Nonetheless, the expression level and biological function of miR-499a-5p in IVDD are still unclear. In this study, we found that miR-499a-5p was significantly downregulated in degenerative tissues of the human nucleus pulposus (NP) compared with healthy tissues. Knockdown of miR-499a-5p promoted NP cell (NPC) apoptosis, stimulated caspase activation, enhanced MMP3 and MMP13 expression, and downregulated aggrecan and type II collagen. Furthermore, TNF-α-treated NPCs showed increased apoptosis and induced an imbalance between anabolism and catabolism of the extracellular matrix (ECM); these changes were attenuated by miR-499a-5p overexpression. Research into possible mechanisms revealed that miR-499a-5p suppressed the expression of SOX4 both at mRNA and protein levels and directly bound to the 3' untranslated region of SOX4 mRNA. Ectopic expression of SOX4 attenuated the negative effect of miR-499a-5p on NPC apoptosis and the positive effect on ECM synthesis. Taken together, these results indicate that miR-499a-5p may attenuate TNF-α-induced NPC apoptosis and an imbalance between anabolism and catabolism of the ECM by downregulating SOX4.
研究表明 microRNAs（miRNAs，miRs）在椎间盘退变（IVDD）的发生发展中发挥着重要作用。然而，miR-499a-5p 在 IVDD 中的表达水平和生物学功能尚不清楚。本研究发现，与健康组织相比，退变的人髓核（NP）组织中 miR-499a-5p 的表达明显下调。下调 miR-499a-5p 可促进 NP 细胞（NPC）凋亡，刺激半胱氨酸天冬氨酸蛋白酶（caspase）激活，增强 MMP3 和 MMP13 的表达，下调聚集蛋白聚糖和 II 型胶原。此外，TNF-α 处理的 NPC 表现出增加的凋亡，并诱导细胞外基质（ECM）的合成与分解代谢失衡；这些变化可被 miR-499a-5p 过表达所减弱。对可能的机制进行研究发现，miR-499a-5p 可在 mRNA 和蛋白水平上抑制 SOX4 的表达，并直接与 SOX4 mRNA 的 3'非翻译区结合。SOX4 的异位表达减弱了 miR-499a-5p 对 NPC 凋亡的负向作用和对 ECM 合成的正向作用。综上，这些结果表明 miR-499a-5p 可能通过下调 SOX4 来减轻 TNF-α 诱导的 NPC 凋亡和 ECM 合成与分解代谢失衡。
