MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology.

Petra Cazzanelli,Karin Wuertz-Kozak

doi:10.3390/ijms21103601

Abstract

Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of protein-coding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.

Highlights

Disc degeneration is a pathological process that leads to the deterioration of intervertebral discs (IVDs), the connective tissue between vertebrae which plays a crucial role in spinal kinematics
Based on the current knowledge provided it is evident that pathological changes in cells of degenerative disc disease (DDD) tissues are associated with the dysregulation of miRNAs and their targets
Future studies should consider investigating the broader miRNA–mRNA network in order to gain a deeper knowledge of the regulatory pathways in DDD pathology

Summary

Introduction

Disc degeneration is a pathological process that leads to the deterioration of intervertebral discs (IVDs), the connective tissue between vertebrae which plays a crucial role in spinal kinematics. In the pathological event of IVD degeneration, the ECM metabolism is dysregulated due to changes in the gene expression and protein secretion of NP cells, leading to increased release of ECM degradative enzymes and decreased production of ECM structural molecules [14] Proteolytic enzymes, such as MMPs and ADAMTS, are mainly responsible for the. The upregulation of miR-21 in degenerated IVD tissue generates higher MMP-3 and MMP-9 expression levels by directly targeting PTEN involved in the Akt signaling pathway [54] Taking these recent studies into account, it becomes evident that miRNAs play a key role in the metabolic dysregulation in IVD pathologies. Another study investigated the use of high MMP levels in the ECM of degenerated IVDs for a novel two-stage delivery system of therapeutic miRNAs by encapsulating them in an outer MMP-degradable hydrogel and an inner MMP-responsive polyplex micelle for injection into IVD [56]

Apoptosis

Inflammation

Mechanobiology

Findings

Conclusions