MicroRNA-140-3p alleviates intervertebral disc degeneration via KLF5/N-cadherin/MDM2/Slug axis. Issue 12 (2nd December 2021)

• Record Type: Journal Article
• Authors: Wang, Zhenyu; Zhang, Shaokun; Zhao, Yuguang; Qu, Zhigang; Zhuang, Xinming; Song, Qingxu; Leng, Jiali; Liu, Yi
• Is Part Of: RNA biology. Volume 18:Issue 12(2021)
• Page Start: 2247
• Page End: 2260
• Publication Date: 2021-12-02
• Subjects: MicroRNA-140-3p -- KLF5 -- N-cadherin -- MDM2 -- slug -- intervertebral disc degeneration -- intervertebral disc nucleus pulposus-derived mesenchymal stem cells; RNA -- Periodicals; Molecular biology -- Periodicals; Molecular biology; RNA; Periodicals; 572.8805
• DOI: 10.1080/15476286.2021.1898176
• Languages: English
• ISSNs: 1547-6286

Abstract

ABSTRACT: MicroRNAs (miRNAs) are associated with healing or deteriorating degenerated intervertebral disc (IVD) tissues in spinal cord diseases, including intervertebral disc degeneration (IDD). IDD represents a chronic process of extracellular matrix destruction, but the relevant molecular mechanisms implicated in the regenerative effects of miRNAs are unclear. Here, we investigated the regenerative effects of microRNA-140 (miR-140-3p) in an IDD model induced by annulus needle puncture. Bioinformatics analysis was conducted to identify regulatory factors (KLF5/N-cadherin/MDM2/Slug) linked to miR-140-3p effects in IDD. Mesenchymal stem cells (MSCs) were extracted from degenerated IVD nucleus pulposus (NP), and the expression of miR-140-3p/KLF5/N-cadherin/MDM2/Slug was manipulated to explore their effects on cell proliferation, migration, apoptosis and differentiation. The results showed that miR-140-3p was under-expressed in the degenerated IVD NP, whereas its overexpression alleviated IDD. Mechanistic studies suggested that miR-140-3p targeted KLF5 expression, and high KLF5 expression impeded the migration and differentiation of MSCs. In degenerated IVD NP-derived MSCs, MiR-140-3p-mediated KLF5 downregulation simultaneously elevated N-cadherin expression and transcriptionally inhibited MDM2, thus upregulating Slug expression. The experimental data indicated that miR-140-3p enhanced the proliferation, migration and differentiation of degenerated IVD NP-derived MSCs and repressed their apoptosis. The in vivo validation experiment also demonstrated that miR-140-3p inhibited IDD by modulating the KLF5/N-cadherin/MDM2/Slug axis. Collectively, our results uncovered the regenerative role of miR-140-3p in IDD via regulation of the KLF5/N-cadherin/MDM2/Slug axis, which could be a potential therapeutic target for IDD. Abbreviations: miR-140-3p: microRNA-140-3p; IDD: intervertebral disc degeneration; MSCs: Mesenchymal stem cells; IVD: intervertebral disc; MSCs: mesenchymal stem cells; KLF5: Kruppel-like factor 5; MDM2: mouse double minute 2; NC: negative control; DHI: disc height index