The Pivotal Role of Nrf2 Signal Axis in Intervertebral Disc Degeneration

Abstract

Intervertebral disc degeneration (IDD) is considered as a dominant contributor to low back pain (LBP), causing severe pain, limited range of lumbar motion, physical dysfunction, and restriction of social activity. However, the specific pathological mechanisms underlying IDD remain elusive, and effective strategies to delay the pathogenesis of IDD are still unclear and limited. In recent years, some studies have found that nuclear factor erythroid 2-related factor 2 (Nrf2), an important antioxidant transcription factor, may play crucial roles in the pathogenesis and progression of age-related diseases including IDD. Nrf2 can maintain redox homeostasis and protecting nucleus pulposus (NP) cells against oxidative stress, inflammatory response, extracellular matrix (ECM) catabolism, cell senescence and cell death involving in the progression of IDD. In this review, we aim to systematically describe the vital roles and pathological mechanism of Nrf2 signaling axis in the pathogenesis of IDD, which may put forward potential therapeutic strategies for the prevention and treatment of IDD by targeting Nrf2.

Keywords:

• Nrf2
• intervertebral disc degeneration
• nucleus pulposus cells
• oxidative stress

Abbreviations

IDD, Intervertebral disc degeneration; LBP, Lower back pain; Nrf2, Nuclear factor erythroid 2-related factor 2; NP, Nucleus pulposus; ECM, Extracellular matrix; IVD, Intervertebral disc; AF, Annulus fibrosus; ROS, Reactive oxygen species; MAPK, Mitogen-activated protein kinase; NF-κB, Nuclear factor kappa-B; GSH, Glutathione; TXN, Thioredoxin; NADPH, Nicotinamide adenine dinucleotide phosphate; GST, Glutathione S-transferase; NQO1, NAD(P)H:quinone oxidoreductase 1; HO-1, Heme oxygenase-1; CNC, Cap “n” Collar; Keap1, Kelch-like ECH associated protein 1; CBP, cAMP-response-element-binding protein; RXRα, Retinoid X receptor α; MAF, Myofascial fibrosarcoma; CHD6, Chromo-ATPase/helicase DNA-binding protein 6; ARE, Antioxidant response element; β-TrCP, β-transducing repeat-containing protein; Gsk-3b, Glycogen synthase kinase-3b; SCF, Skp1-Cul1-F-box; miRNAs, Micro-RNAs; IL-1β, Interleukin 1 beta; TNF-α, Tumor necrosis factor alpha; NO, Nitric oxide; COX-2, Cyclooxygenase-2; ADAMTS-5, A disintegrin and metalloproteinase with thrombospondin motifs-5; PGE2, Prostaglandin E2; MMP-13, Matrix metalloproteinase-13; iNOS, inducible nitric oxide synthase; CO, carbon monoxide; Col2, Collagen-II; PGs, Proteoglycans; GAG, Glycosaminoglycan; MMP3, Matrix metalloproteinase 3; FSS, Fluid shear stress; sGAG, sulfated glycosaminoglycan; H₂O₂, Hydrogen peroxide; NO, Nitric oxide; SASP, Senescence-associated secretory phenotype; SA-β-gal, Senescence-associated beta-galactosidase; SIRT3, Sirtuin3; MnSOD, Manganese superoxide dismutase; ER, Endoplasmic reticulum; LPS, Lipopolysaccharide; NLRP3, NLR family pyrin domain containing 3; PYCARD, PYD and CARD domain containing; GPX4, Glutathione peroxidase 4; DMF, Dimethyl fumarate; PD, Polydatin; C3G, Cyanidin-3-glucoside; QUE, Quercetin; PD, Polydatin; Kin, Kinsenoside; TBHP, Tert-butyl hydroperoxide; BARD, Bardoxolone methyl; Se, Selenium; MDA, Malondialdehyde; SOD2, Superoxide dismutase 2; GSDMD, Gasdermin-D; MFG-E8, Milk fat globules-epidermal growth factor (EGF) factor 8; PRP, Platelet-rich plasma; BMSCs, Bone marrow mesenchymal stem cells; EVs, Extracellular vesicles; HRD, Hesperetin-7-o-rutinoside; Ast, Astaxanthin; FTH1, Ferritin heavy chain 1; SLC7A11, Solute carrier family 7 member 11; PTEN, Phosphatase and tensin homolog; PINK1, (PTEN)-induced putative kinase protein 1; PPARγ, Proliferator-activated receptor gamma; TSG-6, TNF-α-stimulated gene 6 protein; Ad-GDF5, Adenovirus-mediated growth and differentiation factor-5; O-GlcNAcylation, O-linked β-N-cetylglucosaminylation.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declared no conflicts of interest in this work.