Abstract
Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.
Highlights
Lower back pain (LBP), one of the most common musculoskeletal problems in modern society, is responsible for low life quality and a large economic burden [1]
Treatment with tert-butyl hydroperoxide (TBHP) for 24 h reduced the viability of human nucleus pulposus (NP) cells in a dose-dependent manner, and 50 μM TBHP was selected for stimulating cells in subsequent experiments (Figure 1(d))
We examined Superoxide Dismutase (SOD), a key intracellular antioxidant that catalyzes the conversion of superoxide anion (O2–) to H2O2, which is further reduced to H2O and O2; SOD activity in human NP cells was significantly downregulated after TBHP stimulation, and this effect was largely prevented by pretreatment with CUR (Figure 4(d))
Summary
Lower back pain (LBP), one of the most common musculoskeletal problems in modern society, is responsible for low life quality and a large economic burden [1]. The major cause of LBP is widely acknowledged to be intervertebral disc (IVD) degeneration (IDD), an abnormal and cell-mediated response to progressive failure of the IVD due to aging, genetic factors, and various environmental stressors [2]. Oxidative stress has been confirmed to be deeply involved in IDD pathogenesis [6,7,8]. It refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of cells to counteract them through
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