Hartvigsen J, Hancock MJ, Kongsted A, Louw Q, Ferreira ML, Genevay S, et al. What low back pain is and why we need to pay attention. Lancet. 2018;391(10137):2356–67.

Article  PubMed  Google Scholar 

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–858.

Article  Google Scholar 

Vo NV, Hartman RA, Patil PR, Risbud MV, Kletsas D, Iatridis JC, et al. Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res. 2016;34(8):1289–306.

Article  PubMed  PubMed Central  Google Scholar 

Yabe Y, Hagiwara Y, Ando A, Tsuchiya M, Minowa T, Takemura T, et al. Chondrogenic and fibrotic process in the ligamentum flavum of patients with lumbar spinal canal stenosis. Spine (Phila Pa 1976). 2015;40(7):429–35.

Article  PubMed  Google Scholar 

Ding F, Shao ZW, Xiong LM. Cell death in intervertebral disc degeneration. Apoptosis. 2013;18(7):777–85.

Article  PubMed  Google Scholar 

Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44–56.

Article  CAS  PubMed  Google Scholar 

Chen J, Xuan J, Gu YT, Shi KS, Xie JJ, Chen JX, et al. Celastrol reduces IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo. Biomed Pharmacother. 2017;91:208–19.

Article  CAS  PubMed  Google Scholar 

Eun SY, Ko YS, Park SW, Chang KC, Kim HJ. IL-1β enhances vascular smooth muscle cell proliferation and migration via P2Y2 receptor-mediated RAGE expression and HMGB1 release. Vascul Pharmacol. 2015;72:108–17.

Article  CAS  PubMed  Google Scholar 

Tu J, Li W, Zhang Y, Wu X, Song Y, Kang L, et al. Simvastatin Inhibits IL-1β-Induced Apoptosis and Extracellular Matrix Degradation by Suppressing the NF-kB and MAPK Pathways in Nucleus Pulposus Cells. Inflammation. 2017;40(3):725–34.

Article  CAS  PubMed  Google Scholar 

Xu W, Zhang X, Liu G, Zhu M, Wu Y, Jie Z, et al. Oxidative stress abrogates the degradation of KMT2D to promote degeneration in nucleus pulposus. Biochim Biophys Acta Mol Basis Dis. 2020;1866(10): 165888.

Article  CAS  PubMed  Google Scholar 

Liu W, Jin S, Huang M, Li Y, Wang Z, Wang P, et al. Duhuo jisheng decoction suppresses matrix degradation and apoptosis in human nucleus pulposus cells and ameliorates disc degeneration in a rat model. J Ethnopharmacol. 2020;250: 112494.

Article  CAS  PubMed  Google Scholar 

Miwatashi S, Arikawa Y, Kotani E, Miyamoto M, Naruo K, Kimura H, et al. Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent. J Med Chem. 2005;48(19):5966–79.

Article  CAS  PubMed  Google Scholar 

Ji ML, Jiang H, Zhang XJ, Shi PL, Li C, Wu H, et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat Commun. 2018;9(1):5051.

Article  PubMed  PubMed Central  Google Scholar 

Roberts S, Caterson B, Menage J, Evans EH, Jaffray DC, Eisenstein SM. Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine (Phila Pa 1976). 2000;25(23):3005–13.

Article  CAS  PubMed  Google Scholar 

Millward-Sadler SJ, Costello PW, Freemont AJ, Hoyland JA. Regulation of catabolic gene expression in normal and degenerate human intervertebral disc cells: implications for the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther. 2009;11(3):R65.

Article  PubMed  PubMed Central  Google Scholar 

Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310–21.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chang CH, Hsu YM, Chen YC, Lin FH, Sadhasivam S, Loo ST, et al. Anti-inflammatory effects of hydrophilic and lipophilic statins with hyaluronic acid against LPS-induced inflammation in porcine articular chondrocytes. J Orthop Res. 2014;32(4):557–65.

Article  CAS  PubMed  Google Scholar 

Yang C, Cao P, Gao Y, Wu M, Lin Y, Tian Y, et al. Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration. Sci Rep. 2016;6:22182.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Le Maitre CL, Pockert A, Buttle DJ, Freemont AJ, Hoyland JA. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem Soc Trans. 2007;35(Pt 4):652–5.

PubMed  Google Scholar 

Wu X, Liu W, Duan Z, Gao Y, Li S, Wang K, et al. The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration. Sci Rep. 2016;6:30563.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vo NV, Hartman RA, Yurube T, Jacobs LJ, Sowa GA, Kang JD. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J. 2013;13(3):331–41.

Article  PubMed  PubMed Central  Google Scholar 

Wang K, Chen T, Ying X, Zhang Z, Shao Z, Lin J, et al. Ligustilide alleviated IL-1β induced apoptosis and extracellular matrix degradation of nucleus pulposus cells and attenuates intervertebral disc degeneration in vivo. Int Immunopharmacol. 2019;69:398–407.

Article  CAS  PubMed  Google Scholar 

Lu B, Wang C, Wang M, Li W, Chen F, Tracey KJ, et al. Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review. Expert Rev Clin Immunol. 2014;10(6):713–27.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gruber HE, Hoelscher GL, Bethea S, Ingram J, Cox M, Hanley EN Jr. High-mobility group box-1 gene, a potent proinflammatory mediators, is upregulated in more degenerated human discs in vivo and its receptor upregulated by TNF-α exposure in vitro. Exp Mol Pathol. 2015;98(3):427–30.

Article  CAS  PubMed  Google Scholar 

Fang F, Jiang D. IL-1β/HMGB1 signalling promotes the inflammatory cytokines release via TLR signalling in human intervertebral disc cells. Biosci Rep. 2016;36(5): e00379.

Article  PubMed  PubMed Central  Google Scholar 

Tang N, Dong Y, Xiao T, Zhao H. LncRNA TUG1 promotes the intervertebral disc degeneration and nucleus pulposus cell apoptosis though modulating miR-26a/HMGB1 axis and regulating NF-κB activation. Am J Transl Res. 2020;12(9):5449–64.

CAS  PubMed  PubMed Central  Google Scholar 

Yang W, Yu XH, Wang C, He WS, Zhang SJ, Yan YG, et al. Interleukin-1β in intervertebral disk degeneration. Clin Chim Acta. 2015;450:262–72.

Article  CAS  PubMed  Google Scholar 

Zhang CC, Zhou JS, Hu JG, Wang X, Zhou XS, Sun BA, et al. Effects of IGF-1 on IL-1β-induced apoptosis in rabbit nucleus pulposus cells in vitro. Mol Med Rep. 2013;7(2):441–4.

Article  CAS  PubMed  Google Scholar 

Sudo H, Minami A. Regulation of apoptosis in nucleus pulposus cells by optimized exogenous Bcl-2 overexpression. J Orthop Res. 2010;28(12):1608–13.

Article  CAS  PubMed  Google Scholar 

Sudo H, Minami A. Caspase 3 as a therapeutic target for regulation of intervertebral disc degeneration in rabbits. Arthritis Rheum. 2011;63(6):1648–57.

Article  CAS  PubMed  Google Scholar 

Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC. An osmosensing signal transduction pathway in yeast. Science. 1993;259(5102):1760–3.

Article  CAS  PubMed  Google Scholar 

Wuertz K, Vo N, Kletsas D, Boos N. Inflammatory and catabolic signalling in intervertebral discs: the roles of NF-κB and MAP kinases. Eur Cell Mater. 2012;23:103–19.

CAS  PubMed  Google Scholar 

Studer RK, Aboka AM, Gilbertson LG, Georgescu H, Sowa G, Vo N, et al. p38 MAPK inhibition in nucleus pulposus cells: a potential target for treating intervertebral disc degeneration. Spine (Phila Pa 1976). 2007;32(25):2827–33.

Article  PubMed  Google Scholar 

Kim JH, Studer RK, Vo NV, Sowa GA, Kang JD. p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells. Osteoarthritis Cartilage. 2009;17(12):1662–9.

Article  CAS  PubMed  Google Scholar 

Li Y, Mu W, Ren J, Wuermanbieke S, Wahafu T, Ji B, et al. Artesunate alleviates interleukin-1β-induced inflammatory response and apoptosis by inhibiting the NF-κB signaling pathway in chondrocyte-like ATDC5 cells, and delays the progression of osteoarthritis in a mouse model. Int J Mol Med. 2019;44(4):1541–51.

CAS  PubMed  Google Scholar 

Dai S, Shi X, Qin R, Zhang X, Xu F, Yang H.