Role of miR-155 in the regulation of MMP-16 expression in intervertebral disc degeneration

Abstract

The molecular mechanisms of intervertebral disc degeneration (IDD) remain elusive. We found that miR‐155 is down‐regulated in degenerative nucleus pulposus (NP), and more severe degeneration is correlated with higher matrix metallopeptidase 16 (MMP‐16) expression. MMP‐16 also degraded matrix aggrecan. Here, we addressed the in vivo miR‐155‐mediated pathological impact on IDD using a classic puncture mouse model. Lentiviral upregulated‐miR‐155 or downregulated‐miR‐155 was transduced into the discs of C57 mice, which was validated by real‐time polymerase chain reaction (real‐time PCR) and in situ hybridization. Immunohistochemistry and western blotting revealed that up‐regulation of miR‐155 resulted in down‐regulation of MMP‐16 and an increase in aggrecan and collagen type II in mouse NP; whereas, down‐regulation of miR‐155 resulted in up‐regulation of MMP‐16 and a decrease in aggrecan in mouse NP. Radiographic and histological analysis showed that the up‐regulation of miR‐155 attenuated IDD, while down‐regulation of miR‐155 resulted in the deterioration of IDD. These findings indicate that decreased miR‐155 contributed to the up‐regulation of MMP‐16 in vivo, and MMP‐16 further degraded aggrecan and collagen type II, leading to the dehydration and degeneration of discs. Our findings revealed a therapeutic role for miR‐155 in IDD. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1323–1334, 2017.

Long noncoding RNA GAS5 promotes apoptosis in primary nucleus pulposus cells derived from the human intervertebral disc via Bcl‑2 downregulation and caspase‑3 upregulation

“…In the present study, NPC apoptosis-associated lncRNAs were screened by searching the lncRNAs targeted by miR-155. miR-155 expression is decreased in the degenerative NP (10,11); 866 upregulated lncRNAs were confirmed as subjects for analysis in the present study. Additionally, retrieval with TargetScan version 7.0, Ensembl Genome Browser (), UCSC Genome Browser (), and miRBase release 21 () further confirmed the sequence of 631 lncRNAs used for bioinformatics analysis.…”

“…Noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate gene expression in numerous cells, and have been demonstrated to be highly involved in IDD (9). In NPCs, lower levels of miR-155 expression promoted Fas-mediated apoptosis by targeting Fas-associated protein with death domain and caspase-3 (10), and decreased the amount of aggrecan and collagen type II via matrix metalloproteinase (MMP)-16 upregulation (11). Additionally, increasing evidence has suggested the important roles of lncRNAs in IDD, which may serve as novel therapeutic targets for degenerative spinal diseases (12,13).…”

Reconsideration of the Semaphorin-3A Binding Motif Found in Chondroitin Sulfate Using Galnac4s-6st-Knockout Mice

“…Aggrecanases, the collective term for aggrecan-degrading enzymes, are metalloproteinases that belong to a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), a family of extracellular proteases. MMPs and ADAMTS, which are families of metalloproteinases, are considered the most important mediators of aggrecan degradation [36][37][38]. Recent studies have identified MMP-16 as a schizophrenia risk gene [39], and MMP-9 and ADAMTS-5 are implicated in schizophrenia and cerebral cavernous malformations, respectively [40,41].…”

Mitochondrial Pathway Is Involved in Advanced Glycation End Products-Induced Apoptosis of Rabbit Annulus Fibrosus Cells

“…Recent researches have reported that IVD degeneration is related to IVD cell death and the loss of extracellular matrix components, including collagen type II and aggrecan. 15,16 A previous study showed that the accumulation of AGEs and their interaction with AGE receptors in the IVD may lead to decreased aggrecan production, which is responsible for IVD degeneration. 17 Tsai et al 11 reported that AGEs cause matrix degradation accompanied by high MMP-2 expression in disc cells, which promotes disc degeneration.…”