ROS: Crucial Intermediators in the Pathogenesis of Intervertebral Disc Degeneration

Abstract

Excessive reactive oxygen species (ROS) generation in degenerative intervertebral disc (IVD) indicates the contribution of oxidative stress to IVD degeneration (IDD), giving a novel insight into the pathogenesis of IDD. ROS are crucial intermediators in the signaling network of disc cells. They regulate the matrix metabolism, proinflammatory phenotype, apoptosis, autophagy, and senescence of disc cells. Oxidative stress not only reinforces matrix degradation and inflammation, but also promotes the decrease in the number of viable and functional cells in the microenvironment of IVDs. Moreover, ROS modify matrix proteins in IVDs to cause oxidative damage of disc extracellular matrix, impairing the mechanical function of IVDs. Consequently, the progression of IDD is accelerated. Therefore, a therapeutic strategy targeting oxidative stress would provide a novel perspective for IDD treatment. Various antioxidants have been proposed as effective drugs for IDD treatment. Antioxidant supplementation suppresses ROS production in disc cells to promote the matrix synthesis of disc cells and to prevent disc cells from death and senescence in vitro. However, there is not enough in vivo evidence to support the efficiency of antioxidant supplementation to retard the process of IDD. Further investigations based on in vivo and clinical studies will be required to develop effective antioxidative therapies for IDD.

Figure 1

The redox homeostasis of intervertebral disc (IVD) cells. The role of the mitochondrion in reactive oxygen species (ROS) generation of disc cells has been well established. During the transportation of electrons, a small proportion of electrons (1%–3%) leak to produce ROS. However, the nonmitochondrial ROS generation through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase or xanthine oxidase in disc cells remains unknown. Thus, “?” is labeled in these pathways. ROS scavenging is performed by antioxidants and detoxicating enzymes.

Figure 2

Disturbed redox homeostasis in the microenvironment of degenerative IVDs. Excessive reactive oxygen species (ROS) production and impaired antioxidative system exist in degenerative discs.

Figure 3

The involvement of reactive oxygen species (ROS)/oxidative stress in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). ROS activate various signaling pathways in IVD cells and consequently regulate the phenotype, apoptosis, autophagy, and senescence of disc cells. Sustained oxidative stress induced by ROS overproduction reinforces matrix degradation and inflammation and enhances the decrease in the number of viable and functional disc cells in IVDs. Furthermore, ROS alter the extracellular matrix (ECM) structure of IVDs through oxidative modification, impairing the mechanical function of IVDs. As a result, the progression of IDD is accelerated. SASP: senescence-associated secretory phenotype.