title: Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration.
abstract: Intervertebral disc degeneration (IDD) is associated with dysregulated expression of microRNAs (miRNAs). However, the precise molecular mechanisms underlying this disorder remain unclear. Therefore, we tested the hypothesis that miRNAs modulate IDD through effects on the IL-6/STAT3 signaling pathway, a potential regulator of IDD. The miRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing miRNA microarray and quantitative real-time PCR (RT-qPCR). Biological functions of differential expression miRNAs were further investigated using immunofluorescent staining. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 41 miRNAs that were differentially expressed in patients compared with controls. Following RT-qPCR confirmation, miR-98 was significantly downregulated in degenerative NP tissues. Moreover, its level was inversely correlated with grade of disc degeneration. Through gain-of-function and loss-of-function studies, miR-98 was shown to significantly promote type II collagen expression in NP cells. Interleukin-6 (IL-6) was identified as a target of miR-98. Knockdown of IL-6 induced effects on NP cells similar to those induced by miR-98. In contrast, IL-6 treatment abrogated the effects induced by miR-98 upregulation. Moreover, miR-98 dramatically suppressed expression of STAT3 target gene, MMP2. IL-6 treatment antagonized this effect, whereas knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-STAT3 and its main target genes, similar to miR-98. The mRNA level of IL-6 was inversely correlated with that of miR-98 in degenerative NP tissues. These results suggest the downregulation of miR-98 could promote IDD through the IL-6/STAT3 signaling pathway. Our findings also highlight miR-98 as a novel hopeful therapeutic target for IDD.
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Ming-liang
authors.initials: ML
authors.lastname: Ji
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing, China.
authors.forename: Pei-liang
authors.initials: PL
authors.lastname: Shi
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Xue-jun
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Shan-zheng
authors.initials: SZ
authors.lastname: Wang
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D055959:Intervertebral Disc Degeneration / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C546084:MIRN98 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: IL-6/STAT3 SIGNALING PATHWAY; INTERVERTEBRAL DISC DEGENERATION; MIR-98