Mitochondrial‐derived reactive oxygen species (ROS) play a causal role in aging‐related intervertebral disc degeneration

Abstract

Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O2) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O2). Human disc cells grown at 20% O2 showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O2. Importantly, we demonstrated that treatment of accelerated aging Ercc1−/Δmice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1−/Δmice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

“…Here, we identified FOXO3 as a novel mediator of NP cell adaptation to hypoxia and demonstrated that FOXO3 and, to a lesser extent, FOXO1 regulate the expression of autophagy genes and activation in NP cells. Although a causal relationship between autophagy defects and IDD has not yet been established, our findings showed that FOXO function promotes NP cell survival under oxidative and inflammatory stresses, major drivers of NP cell apoptosis and aging‐related IDD (Nasto et al, 2013; Wang et al, 2013; Yang et al, 2014), and thus suggest that activation of FOXO in aged IVD could increase autophagy and protect NP cells from stress‐induced apoptosis. Further supporting this hypothesis, various studies have shown that autophagy activation can protect NP cells against different apoptotic insults (Jiang, Jin, Wang, Jiang, & Dong, 2014; Jiang, Zhang, et al, 2014).…”

Effects of rhein lysinate on D-galactose-induced aging mice

“…Aging model mice are characterized by an increased concentration of ROS and a significant reduction in their antioxidant defenses (32). ROS are chemically reactive oxygen-derived molecules.…”

Whether reactive oxygen species plays a critical role in intrinsic (mitochondrial) pathway-mediated apoptosis in notochordal cells under high glucose concentrations?

“…Kim et al [3] found that oxidative stress caused apoptosis of rat notochordal cells via both intrinsic and extrinsic pathways. Nasto et al [4] found that mitochondrial-derived reactive oxygen species play a causal role in age-related intervertebral disc degeneration.Third, antioxidants may be a novel treatment option for disc degeneration. Recent studies have shown that ferulic acid (FA) [5] and resveratrol possess excellent antioxidant and antiinflammatory properties, can treat nucleus pulposus cells from the damage caused by oxidative stress and may have considerable promise in the treatment of disc degeneration.…”

“…Kim et al [3] found that oxidative stress caused apoptosis of rat notochordal cells via both intrinsic and extrinsic pathways. Nasto et al [4] found that mitochondrial-derived reactive oxygen species play a causal role in age-related intervertebral disc degeneration.…”