MicroRNA-25-3p therapy for intervertebral disc degeneration by targeting the IL-1β/ZIP8/MTF1 signaling pathway with a novel thermo-responsive vector

Yong Huang; Leizhen Huang; Li Li; Zhishen Ge; Ganjun Feng; Limin Liu; Yueming Song

doi:10.21037/atm-20-6595

MicroRNA-25-3p therapy for intervertebral disc degeneration by targeting the IL-1β/ZIP8/MTF1 signaling pathway with a novel thermo-responsive vector

Ann Transl Med. 2020 Nov;8(22):1500. doi: 10.21037/atm-20-6595.

Authors

Yong Huang¹, Leizhen Huang¹, Li Li², Zhishen Ge³, Ganjun Feng¹, Limin Liu¹, Yueming Song¹

Affiliations

¹ Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China.
² Department of Science and Technology, West China Hospital, Sichuan University, Chengdu, China.
³ CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.

Abstract

Background: MicroRNAs play important roles in intervertebral disc degeneration (IDD). The therapeutic effects of miRNA-25-3p on IDD and underlying mechanism are unclear.

Methods: Normal and degenerated nuclear pulposus (NP) tissue were collected. Primary NP cells were isolated and treated with different concentrations of interleukin-1β (IL-1β). IL-1β treated NP cells were interfered with miRNA-25-3p. Associated proteins IL-1β, ZIP8, MTF1, extracellular matrix (ECM) degrading enzymes MMP3, MMP13, ADAMTS5, ECM proteins type II collagen, aggrecan and MiRNA-25-3p were detected by western blotting or qRT-PCR method. Dual luciferase reporter assays were performed to determine potential targets MTF1 of miRNA-25-3p. In vitro miRNA-25-3p transfection efficiency of thermos-responsive vector was observed by fluorescence microscopy. Animal studies were conducted to observe the therapeutic effects of miRNA-25-3p mimic delivered by thermo-responsive vector.

Results: Compared with normal NP tissues, IL-1β, ZIP8 and MTF1 significantly increased and miRNA-25-3p significantly decreased in degenerated tissues. IL-1β promotes the expression of ZIP8 and nuclear translocation of MTF1 in NP cells. Ultimately, it promotes expression of ECM degrading enzymes and inhibits synthesis of ECM protein. MiRNA- 25-3p could inhibit the effects of IL-1β and the expression of ECM degrading enzymes, and recover the expression of ECM protein. Further investigation showed MTF1 was a target protein of miRNA-25-3p. The thermo-responsive vector could effectively deliver miRNA-25-3p into NP cells. Animal studies demonstrated miRNA-25-3p delivered by the thermo-responsive vector can delay progression of IDD.

Conclusions: The thermo-responsive vector delivering miRNA-25-3p could delay the progression of IDD by inhibiting IL-1β-induced effects, and may be potential therapy for IDD in future.

Keywords: IL-1β; Intervertebral disc degeneration (IDD); MTF1; miRNA-25-3p; thermo-responsive vector.