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Literature Reviews.

Contribution of immune cells to intervertebral disc degeneration and the potential of immunotherapy

, , & ORCID Icon
Pages 413-427 | Received 27 Jul 2022, Accepted 03 May 2023, Published online: 17 May 2023

References

  • Andersson GBJ. Epidemiological features of chronic low-back pain. Lancet. 1999;354(9178):581–585. doi:10.1016/S0140-6736(99)01312-4.
  • Katz JN. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J Bone Joint Surg Am. 2006;88(Suppl 2):21–24. doi:10.2106/JBJS.E.01273.
  • Freemont AJ, Peacock TE, Goupille P, Hoyland JA, O’Brien J, Jayson M. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet. 1997;350(9072):178–181. doi:10.1016/S0140-6736(97)02135-1.
  • Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, Cheah KS, Leong JC, Luk KD. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine. 2009;34(9):934–940; (Phila Pa 1976).
  • Roberts S, Evans H, Trivedi J, Menage J. Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am. 2006;88(Suppl 2):10–14. doi:10.2106/JBJS.F.00019.
  • Hayes AJ, Benjamin M, Ralphs JR. Extracellular matrix in development of the intervertebral disc. Matrix Biol. 2001;20(2):107–121. doi:10.1016/S0945-053X(01)00125-1.
  • Hutton WC ea. Does long-term compressive loading on the intervertebral disc cause degeneration? Spine. 2000;25(23):2993–3004. doi:10.1097/00007632-200012010-00006.
  • Urban JP, Roberts S. Degeneration of the intervertebral disc. Arthritis Res Ther. 2003;5(3):120–130. doi:10.1186/ar629.
  • Eyre DM. Quantitative analysis of types I and II collagens in the human intervertebral disc at various ages. Biochim Biophys Acta. 1977;492(1):29–42. doi:10.1016/0005-2795(77)90211-2.
  • Johnstone BB. The large proteoglycans of the human intervertebral disc. Changes in their biosynthesis and structure with age, topography, and pathology. Spine. 1995;20(6):674–684. doi:10.1097/00007632-199503150-00008.
  • de Schepper EI, Damen J, van Meurs JB, Ginai AZ, Popham M, Hofman A, Koes BW, Bierma-Zeinstra SM. The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features. Spine. 2010;35(5):531–536. doi:10.1097/BRS.0b013e3181aa5b33.
  • Russo F, Hartman RA, Bell KM, Vo N, Sowa GA, Kang JD, Vadala, G, Denaro, V. Biomechanical evaluation of transpedicular nucleotomy with intact annulus fibrosus. Spine. 2017;42(4):E193–201. doi:10.1097/BRS.0000000000001762. (Phila Pa 1976).
  • Nasto LA, Ngo K, Leme AS, Robinson AR, Dong Q, Roughley P, Usas A, Sowa GA, Pola E, Kang, J. Investigating the role of DNA damage in tobacco smoking-induced spine degeneration. Spine J. 2014;14(3):416–423. doi:10.1016/j.spinee.2013.08.034.
  • Zhang TW, Li ZF, Dong J, Jiang LB. The circadian rhythm in intervertebral disc degeneration: an autophagy connection. Experimental & Molecular Medicine. 2020;52(1):31–40. doi:10.1038/s12276-019-0372-6.
  • Cannata F, Vadala G, Ambrosio L, Fallucca S, Napoli N, Papalia R, Pozzilli P, Denaro V. Intervertebral disc degeneration: a focus on obesity and type 2 diabetes. Diabetes Metab Res Rev. 2020;36(1):e3224. doi:10.1002/dmrr.3224.
  • Francisco V, Pino J, Gonzalez-Gay MA, Lago F, Karppinen J, Tervonen O, Mobasheri A, Gualillo O. A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol. 2022;18(1):47–60. doi:10.1038/s41584-021-00713-z.
  • Wang F, Cai F, Shi R, Wang XH, Wu XT. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage. 2016;24(3):398–408. doi:10.1016/j.joca.2015.09.019.
  • Johnson WE, Roberts S. Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connect Tissue Res. 2001;42(3):197–207. doi:10.3109/03008200109005650.
  • Gruber HE, Hanley EN Jr. Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine. 1998;23(7):751–757. doi:10.1097/00007632-199804010-00001. (Phila Pa 1976)
  • Trout JJ, Buckwalter JA, Moore KC. Ultrastructure of the human intervertebral disc: iI. Cells of the nucleus pulposus. Anat Rec. 1982;204(4):307–314. doi:10.1002/ar.1092040403.
  • Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine. 2006;31(18):2151–2161. doi:10.1097/01.brs.0000231761.73859.2c. (Phila Pa 1976)
  • Freemont AJ, Watkins A, Le Maitre C, Baird P, Jeziorska M, Knight MT, Ross ER, O brien JP, Hoyland JA. Nerve growth factor expression and innervation of the painful intervertebral disc. J Pathol. 2002;197(3):286–292. doi:10.1002/path.1108.
  • Kauppila LI. Ingrowth of blood vessels in disc degeneration. Angiographic and histological studies of cadaveric spines. J Bone Joint Surg Am. 1995;77(1):26–31. doi:10.2106/00004623-199501000-00004.
  • Iatridis JC, Nicoll SB, Michalek AJ, Walter BA, Gupta MS. Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? Spine J. 2013;13(3):243–262. doi:10.1016/j.spinee.2012.12.002.
  • Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine. 2001;26(17):1873–1878. doi:10.1097/00007632-200109010-00011. (Phila Pa 1976)
  • Weiler C, Schietzsch M, Kirchner T, Nerlich AG, Boos N, Wuertz K. Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation. Eur Spine J. 2012;21(Suppl S6):S810–8. doi:10.1007/s00586-011-1922-3.
  • Latridis JC, Godburn K, Wuertz K, Alini M, Roughley PJ. Region-dependent aggrecan degradation patterns in the rat intervertebral disc are affected by mechanical loading in vivo. Spine. 2011;36(3):203–209. doi:10.1097/BRS.0b013e3181cec247. (Phila Pa 1976)
  • Jim B, Steffen T, Moir J, Roughley P, Haglund L. Development of an intact intervertebral disc organ culture system in which degeneration can be induced as a prelude to studying repair potential. Eur Spine J. 2011;20(8):1244–1254. doi:10.1007/s00586-011-1721-x.
  • Roughley PJ, Melching LI, Heathfield TF, Pearce RH, Mort JS. The structure and degradation of aggrecan in human intervertebral disc. Eur Spine J. 2006;15(Suppl S3):S326–32. doi:10.1007/s00586-006-0127-7.
  • Sato K, Kikuchi S, Yonezawa T. In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems. Spine. 1999;24(23):2468–2474. doi:10.1097/00007632-199912010-00008. (Phila Pa 1976)
  • Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, Aebi M, Alini M. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest. 1996;98(4):996–1003. doi:10.1172/JCI118884.
  • Vergroesen PP, Kingma I, Emanuel KS, Hoogendoorn RJ, Welting TJ, van Royen BJ, van Dieën JH, Smit TH. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthritis Cartilage. 2015;23(7):1057–1070. doi:10.1016/j.joca.2015.03.028.
  • Smith RL, Carter DR, Schurman DJ. Pressure and shear differentially alter human articular chondrocyte metabolism - a review. Clin Orthop Relat R. 2004;(427):S89–95.
  • Liu GZ, Ishihara H, Osada R, Kimura T, Tsuji H. Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hydrostatic pressure. Spine. 2001;26(2):134–141. doi:10.1097/00007632-200101150-00005. (Phila Pa 1976)
  • Hsieh AW, Cheng LY, Lotz JC Apoptosis corresponds with disc strain environment during dynamic compression. In: Transactions of the 50th Annualmeeting of the Orthopaedic Research Society. 2004.
  • Kepler CK, Markova DZ, Hilibrand AS, Vaccaro AR, Risbud MV, Albert TJ, Anderson DG. Substance P stimulates production of inflammatory cytokines in human disc cells. Spine. 2013;38(21):E1291–9. doi:10.1097/BRS.0b013e3182a42bc2. (Phila Pa 1976).
  • Rand N, Reichert F, Floman Y, Rotshenker S. Murine nucleus pulposus-derived cells secrete interleukins-1-beta, -6, and -10 and granulocyte-macrophage colony-stimulating factor in cell culture. Spine. 1997;22(22):2598–2601. doi:10.1097/00007632-199711150-00002. (Phila Pa 1976) discussion 602
  • Yamamoto J, Maeno K, Takada T, Kakutani K, Yurube T, Zhang Z, Hirata H, Kurakawa T, Sakai D, Mochida J, Doita M. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res. 2013;31(4):608–615. doi:10.1002/jor.22274.
  • Gentek R, Molawi K, Sieweke MH. Tissue macrophage identity and self-renewal. Immunol Rev. 2014;262(1):56–73. doi:10.1111/imr.12224.
  • Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–455. doi:10.1038/nature12034.
  • Huang YC, Urban JPG, Luk KDK. Intervertebral disc regeneration: do nutrients lead the way? Nat Rev Rheumatol. 2014;10(9):561–566. doi:10.1038/nrrheum.2014.91.
  • Oki S, Matsuda Y, Shibata T, Okumura H, Desaki J. Morphologic differences of the vascular buds in the vertebral endplate: scanning electron microscopic study. Spine. 1996;21(2):174–177. doi:10.1097/00007632-199601150-00003. (Phila Pa 1976)
  • Roberts S, Menage J, Urban JP. Biochemical and structural properties of the cartilage end-plate and its relation to the intervertebral disc. Spine. 1989;14(2):166–174. doi:10.1097/00007632-198902000-00005. (Phila Pa 1976)
  • Ratcliffe JF. The arterial anatomy of the adult human lumbar vertebral body: a microarteriographic study. J Anat. 1980;131(Pt 1):57–79.
  • Ashinsky B, Smith HE, Mauck RL, Gullbrand SE. Intervertebral disc degeneration and regeneration: a motion segment perspective. Eur Cell Mater. 2021;41:370–387. doi:10.22203/eCM.v041a24.
  • Sun Z, Liu B, Luo ZJ. The Immune Privilege of the Intervertebral Disc: implications for Intervertebral Disc Degeneration Treatment. Int J Med Sci. 2020;17(5):685–692. doi:10.7150/ijms.42238.
  • Jill PG, Urban P, Smith S, Phil D, Jeremy CT, Fairbank MD, FRCS†, Jill PG, Urban P, Smith S, Phil D, Jeremy CT, Fairbank MD, Nutrition of the intervertebral disc. Spine. 2004;29(23):2700–2709. doi:10.1097/01.brs.0000146499.97948.52.
  • Hee HT, Chuah YJ, Tan BH, Setiobudi T, Wong HK. Vascularization and morphological changes of the endplate after axial compression and distraction of the intervertebral disc. Spine. 2011;36(7):505–511. doi:10.1097/BRS.0b013e3181d32410. (Phila Pa 1976)
  • Zhen Sun ZY, Guo YS, Wang HQ, Luo ZJ. FasL on human nucleus pulposus cells prevents angiogenesis in the disc by inducing Fas-mediated apoptosis of vascular endothelial cells. Int J Clin Exp Pathol. 2013;6(11):2376–2385.
  • Liu ZH, Sun Z, Wang HQ, Ge J, Jiang TS, Chen YF, Ma Y, Wang C, Hu S, Samartzis D, Luo ZJ. FasL expression on human nucleus pulposus cells contributes to the immune privilege of intervertebral disc by interacting with immunocytes. Int J Med Sci. 2013;10(8):1053–1060. doi:10.7150/ijms.6223.
  • Takada T, Nishida K, Doita M, Kurosaka M. Fas ligand exists on intervertebral disc cells: a potential molecular mechanism for immune privilege of the disc. Spine. 2002;27(14):1526–1530. doi:10.1097/00007632-200207150-00009. (Phila Pa 1976)
  • Kaneyama S, Nishida K, Takada T, Suzuki T, Shimomura T, Maeno K, Kurosaka M, Doita M. Fas ligand expression on human nucleus pulposus cells decreases with disc degeneration processes. J Orthop Sci. 2008;13(2):130–135. doi:10.1007/s00776-007-1204-4.
  • Nakazawa KR, Walter BA, Laudier DM, Krishnamoorthy D, Mosley GE, Spiller KL, Iatridis JC. Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration. Spine J. 2018;18(2):343–356. doi:10.1016/j.spinee.2017.09.018.
  • Zhen Sun MZ, Zhao XH, Liu ZH, Gao Y, Samartzis D, Wang HQ, Luo ZJ. Immune cascades in human intervertebral disc: the pros and cons. Int J Clin Exp Pathol. 2013;6(6):1009–1014.
  • Stemple DL. Structure and function of the notochord: an essential organ for chordate development. Development. 2005;132(11):2503–2512. doi:10.1242/dev.01812.
  • Kim KW, Lim TH, Kim JG, Jeong ST, Masuda K, An HS. The origin of chondrocytes in the nucleus pulposus and histologic findings associated with the transition of a notochordal nucleus pulposus to a fibrocartilaginous nucleus pulposus in intact rabbit intervertebral discs. Spine. 2003;28(10):982–990. doi:10.1097/01.BRS.0000061986.03886.4F. (Phila Pa 1976)
  • Cornejo MC, Cho SK, Giannarelli C, Iatridis JC, Purmessur D. Soluble factors from the notochordal-rich intervertebral disc inhibit endothelial cell invasion and vessel formation in the presence and absence of pro-inflammatory cytokines. Osteoarthritis Cartilage. 2015;23(3):487–496. doi:10.1016/j.joca.2014.12.010.
  • Gan Y, He J, Zhu J, Xu Z, Wang Z, Yan J, Hu O, Bai Z, Chen L, Xie Y, Jin M. Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs. Bone Res. 2021;9(1):37. doi:10.1038/s41413-021-00163-z.
  • Richardson SM, Ludwinski FE, Gnanalingham KK, Atkinson RA, Freemont AJ, Hoyland JA. Notochordal and nucleus pulposus marker expression is maintained by sub-populations of adult human nucleus pulposus cells through aging and degeneration. null. 2017;7(1):1501. doi:10.1038/s41598-017-01567-w.
  • Rodrigues-Pinto R, Ward L, Humphreys M, Zeef LAH, Berry A, Hanley KP, Hanley N, Richardson SM, Hoyland JA. Human notochordal cell transcriptome unveils potential regulators of cell function in the developing intervertebral disc. null. 2018;8(1):12866.
  • Walmsley R. The development and growth of the intervertebral disc. Edinb Med J. 1953;60(8):341–364.
  • Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006;209(2):157–165. doi:10.1002/path.1969.
  • Aguiar DJ, Johnson SL, Oegema TR. Notochordal cells interact with nucleus pulposus cells: regulation of proteoglycan synthesis. Exp Cell Res. 1999;246(1):129–137. doi:10.1006/excr.1998.4287.
  • Cappello R, Bird JLE, Pfeiffer D, Bayliss MT, Dudhia J. Notochordal cell produce and assemble extracellular matrix in a distinct manner, which may be responsible for the maintenance of healthy nucleus pulposus. Spine. 2006;31:873–882. doi:10.1097/01.brs.0000209302.00820.fd.
  • de Vries SA, Potier E, van Doeselaar M, Meij BP, Tryfonidou MA, Ito K. Conditioned medium derived from notochordal cell-rich nucleus pulposus tissue stimulates matrix production by canine nucleus pulposus cells and bone marrow-derived stromal cells. Tissue Eng Part A. 2015;21(5–6):1077–1084. doi:10.1089/ten.tea.2014.0309.
  • Erwin WM, Islam D, Inman RD, Fehlings MG, Tsui FW. Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration. Arthritis Res Ther. 2011;13(6):R215. doi:10.1186/ar3548.
  • Johnson WE, Caterson B, Eisenstein SM, Roberts S. Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro. Spine. 2005;30(10):1139–1147. doi:10.1097/01.brs.0000162624.95262.73. (Phila Pa 1976)
  • Purmessur D, Cornejo MC, Cho SK, Roughley PJ, Linhardt RJ, Hecht AC, Iatridis, JC. Intact glycosaminoglycans from intervertebral disc-derived notochordal cell-conditioned media inhibit neurite growth while maintaining neuronal cell viability. Spine J. 2015;15(5):1060–1069. doi:10.1016/j.spinee.2015.02.003.
  • Kim JH, Moon HJ, Lee JH, Kim JH, Kwon TH, Park YK. Rabbit notochordal cells modulate the expression of inflammatory mediators by human annulus fibrosus cells cocultured with activated macrophage-like THP-1 cells. Spine. 2012;37(22):1856–1864. doi:10.1097/BRS.0b013e3182579434. (Phila Pa 1976)
  • Masakazu Yoshida TN, Kikuchi T, Takagi K, Matsukawa A. Expression of monocyte chemoattractant protein- 1 in primary cultures of rabbit intervertebral disc cells. J Orthop Res. 2002;20:1298–1304. doi:10.1016/S0736-0266(02)00060-8.
  • Louman-Gardiner KM, Coombe D, Hunter CJ. Computation models simulating notochordal cell extinction during early ageing of an intervertebral disc. Comput Methods Biomech Biomed Engin. 2011;14(12):1071–1077. doi:10.1080/10255842.2010.508037.
  • Weiler C, Nerlich AG, Schaaf R, Bachmeier BE, Wuertz K, Boos N. Immunohistochemical identification of notochordal markers in cells in the aging human lumbar intervertebral disc. Eur Spine J. 2010;19(10):1761–1770. doi:10.1007/s00586-010-1392-z.
  • McCann MR, Tamplin OJ, Rossant J, Seguin CA. Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development. Dis Model Mech. 2012;5(1):73–82. doi:10.1242/dmm.008128.
  • Risbud MV, Shapiro IM. Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr. 2011;21(1):29–41. doi:10.1615/CritRevEukarGeneExpr.v21.i1.30.
  • Risbud MV, Schoepflin ZR, Mwale F, Kandel RA, Grad S, Iatridis JC, Sakai D, Hoyland JA. Defining the phenotype of young healthy nucleus pulposus cells: recommendations of the spine research interest group at the 2014 annual ORS meeting. J Orthop Res. 2015;33(3):283–293.
  • Choi KS, Cohn MJ, Harfe BD. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Dev Dyn. 2008;237(12):3953–3958. doi:10.1002/dvdy.21805.
  • Shamji MF, Setton LA, Jarvis W, So S, Chen J, Jing L, Bullock R, Isaacs RE, Brown C, Richardson WJ. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 2010;62(7):1974–1982. doi:10.1002/art.27444.
  • Silva AJ, Ferreira JR, Cunha C, Corte-Real JV, Bessa-Goncalves M, Barbosa MA, Santos SG, Gonçalves RM. Macrophages down-regulate gene expression of intervertebral disc degenerative markers under a pro-inflammatory microenvironment. Front Immunol. 2019;10:1508.
  • Yang C, Cao P, Gao Y, Wu M, Lin Y, Tian Y, Yuan W. Differential expression of p38 MAPK alpha, beta, gamma, delta isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration. null. 2016;6:22182.
  • Kokubo Y, Uchida K, Kobayashi S, Yayama T, Sato R, Nakajima H, Takamura T, Mwaka E, Orwotho N, Bangirana A, Baba, H. Herniated and spondylotic intervertebral discs of the human cervical spine: histological and immunohistological findings in 500 en bloc surgical samples. Lab Invest J Neurosurg Spine. 2008;9(3):285–295. doi:10.3171/SPI/2008/9/9/285.
  • Binch AAC AL, Breakwell LM, Michael AL, Chiverton N, Cross1 AK, Le Maitre CL. Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration. Arthritis Res Ther. 2014;16(4). doi:10.1186/s13075-014-0416-1.
  • Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44–56. doi:10.1038/nrrheum.2013.160.
  • Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–189. doi:10.1189/jlb.0603252.
  • Habtemariam A, Gronblad M, Virri J, Seitsalo S, Karaharju E. A comparative immunohistochemical study of inflammatory cells in acute-stage and chronic-stage disc herniations. Spine. 1998;23(20):2159–2165. doi:10.1097/00007632-199810150-00003. (Phila Pa 1976) discussion 66
  • Bermudez-Lekerika P, Crump KB, Tseranidou S, Nuesch A, Kanelis E, Alminnawi A, Baumgartner, L, Muñoz-Moya, E, Compte R, Gualdi F, Alexopoulos LG. Immuno-modulatory effects of intervertebral disc cells. Front Cell Dev Biol. 2022;10:924692.
  • Murai K, Sakai D, Nakamura Y, Nakai T, Igarashi T, Seo N, Murakami T, Kobayashi E, Mochida J. Primary immune system responders to nucleus pulposus cells: evidence for immune response in disc herniation. Eur Cell Mater. 2010;19:13–21.
  • Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. 2010;3(105):cm1. doi:10.1126/scisignal.3105cm1.
  • Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6(4):232–241. doi:10.1038/nrrheum.2010.4.
  • Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther. 2005;7(4):R732–45. doi:10.1186/ar1732.
  • Seguin CA, Pilliar RM, Roughley PJ, Kandel RA. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine. 2005;30(17):1940–1948. doi:10.1097/01.brs.0000176188.40263.f9. (Phila Pa 1976)
  • Wang J, Markova D, Anderson DG, Zheng Z, Shapiro IM, Risbud MV. TNF-alpha and IL-1beta promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem. 2011;286(46):39738–39749. doi:10.1074/jbc.M111.264549.
  • Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, Risbud MV. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-kappaB. Am J Pathol. 2013;182(6):2310–2321. doi:10.1016/j.ajpath.2013.02.037.
  • Gabr MA, Jing L, Helbling AR, Sinclair SM, Allen KD, Shamji MF. Interleukin-17 synergizes with IFNgamma or TNFalpha to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells. J Orthop Res. 2011;29(1):1–7. doi:10.1002/jor.21206.
  • Phillips KL, Cullen K, Chiverton N, Michael AL, Cole AA, Breakwell LM, Haddock G, Bunning RA, Cross AK, Le Maitre CL. Potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes. Osteoarthritis Cartilage. 2015;23(7):1165–1177. doi:10.1016/j.joca.2015.02.017.
  • Jones P, Gardner L, Menage J, Williams GT, Roberts S. Intervertebral disc cells as competent phagocytes in vitro: implications for cell death in disc degeneration. Arthritis Res Ther. 2008;10(4):R86. doi:10.1186/ar2466.
  • Nerlich AG, Weiler C, Zipperer J, Narozny M, Boos N. Immunolocalization of phagocytic cells in normal and degenerated intervertebral discs. Spine. 2002;27(22):2484–2490. (Phila Pa 1976).
  • Ivashkiv LB. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 2013;34(5):216–223. doi:10.1016/j.it.2012.11.001.
  • Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. doi:10.1016/j.immuni.2014.06.008.
  • Lurier EB, Dalton D, Dampier W, Raman P, Nassiri S, Ferraro NM, Rajagopalan R, Sarmady M, Spiller KL. Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing. Immunobiology. 2017;222(7):847–856. doi:10.1016/j.imbio.2017.02.006.
  • Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020;877:173090. doi:10.1016/j.ejphar.2020.173090.
  • Kim H, Wang SY, Kwak G, Yang Y, Kwon IC, Kim SH. Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing. Adv Sci (Weinh). 2019;6(20):1900513. doi:10.1002/advs.201900513.
  • Kang H, Kim S, Wong DSH, Jung HJ, Lin S, Zou K, Li R, Li G, Dravid VP, Bian L. Remote manipulation of ligand nano-oscillations regulates adhesion and polarization of macrophages in vivo. Nano Lett. 2017;17(10):6415–6427. doi:10.1021/acs.nanolett.7b03405.
  • Kim TH, Kang MS, Mandakhbayar N, El-Fiqi A, Kim HW. Anti-inflammatory actions of folate-functionalized bioactive ion-releasing nanoparticles imply drug-free nanotherapy of inflamed tissues. Biomaterials. 2019;207:23–38. doi:10.1016/j.biomaterials.2019.03.034.
  • Kim J, Kim HY, Song SY, Go SH, Sohn HS, Baik S, Soh M, Kim K, Kim D, Kim HC, Lee N. Synergistic oxygen generation and reactive oxygen species scavenging by manganese ferrite/ceria co-decorated nanoparticles for rheumatoid arthritis Treatment. Acs Nano. 2019;13(3):3206–3217. doi:10.1021/acsnano.8b08785.
  • Yan M, Song Z, Kou H, Shang G, Shang C, Chen X, Ji Y, Bao D, Cheng T, Li J, Lv X. New progress in basic research of macrophages in the pathogenesis and treatment of low back pain. Front Cell Dev Biol. 2022;10:866857.
  • Djuric N, Lafeber GCM, Vleggeert-Lankamp CLA. The contradictory effect of macrophage-related cytokine expression in lumbar disc herniations: a systematic review. Eur Spine J. 2020;29(7):1649–1659. doi:10.1007/s00586-019-06220-w.
  • Phillips KL, Chiverton N, Michael AL, Cole AA, Breakwell LM, Haddock G, Bunning RA, Cross AK, Le Maitre CL. The cytokine and chemokine expression profile of nucleus pulposus cells: implications for degeneration and regeneration of the intervertebral disc. Arthritis Res Ther. 2013;15(6):R213. doi:10.1186/ar4408.
  • Wang J, Tian Y, Phillips KL, Chiverton N, Haddock G, Bunning RA. Tumor necrosis factor alpha- and interleukin-1beta-dependent induction of CCL3 expression by nucleus pulposus cells promotes macrophage migration through CCR1. Arthritis Rheum. 2013;65(3):832–842. doi:10.1002/art.37819.
  • Nakawaki M, Uchida K, Miyagi M, Inoue G, Kawakubo A, Kuroda A. Sequential CCL2 expression profile after disc injury in mice. J Orthop Res. 2020;38(4):895–901. doi:10.1002/jor.24522.
  • Li Z, Wang X, Pan H, Yang H, Li X, Zhang K, Wang H, Zheng Z, Liu H, Wang J. Resistin promotes CCL4 expression through toll-like receptor-4 and activation of the p38-MAPK and NF-kappaB signaling pathways: implications for intervertebral disc degeneration. Osteoarthritis Cartilage. 2017;25(2):341–350. doi:10.1016/j.joca.2016.10.002.
  • Kepler CK, Markova DZ, Dibra F, Yadla S, Vaccaro AR, Risbud MV, Albert TJ, Anderson DG. Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1beta in painful human intervertebral discs. Spine. 2013;38(11):873–880. (phila Pa 1976). doi:10.1097/BRS.0b013e318285ae08.
  • Ansari N, Abdulla J, Zayyani N, Brahmi U, Taha S, Satir AA. Comparison of RANTES expression in Crohn’s disease and ulcerative colitis: an aid in the differential diagnosis? J Clin Pathol. 2006;59(10):1066–1072. doi:10.1136/jcp.2005.034983.
  • Denes A, Humphreys N, Lane TE, Grencis R, Rothwell N. Chronic systemic infection exacerbates ischemic brain damage via a CCL5 (regulated on activation, normal T-cell expressed and secreted)-mediated proinflammatory response in mice. J Neurosci. 2010;30(30):10086–10095. doi:10.1523/JNEUROSCI.1227-10.2010.
  • Jones KL, Maguire JJ, Davenport AP. Chemokine receptor CCR5: from AIDS to atherosclerosis. Br J Pharmacol. 2011;162(7):1453–1469. doi:10.1111/j.1476-5381.2010.01147.x.
  • Muller K, Aichele S, Herkommer M, Bigalke B, Stellos K, Htun P. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis. 2010;213(1):256–262. doi:10.1016/j.atherosclerosis.2010.07.023.
  • Pai JK, Kraft P, Cannuscio CC, Manson JE, Rexrode KM, Albert CM, Hunter D, Rimm EB. Polymorphisms in the CC-chemokine receptor-2 (CCR2) and -5 (CCR5) genes and risk of coronary heart disease among US women. Atherosclerosis. 2006;186(1):132–139. doi:10.1016/j.atherosclerosis.2005.06.041.
  • Pavlova EV, Deegan PB, Tindall J, McFarlane I, Mehta A, Hughes D. Potential biomarkers of osteonecrosis in Gaucher disease. Blood Cells Mol Dis. 2011;46(1):27–33. doi:10.1016/j.bcmd.2010.10.010.
  • Schober A. Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol. 2008;28(11):1950–1959. doi:10.1161/ATVBAHA.107.161224.
  • Szalai C, Duba J, Prohaszka Z, Kalina A, Szabo T, Nagy B. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients. Atherosclerosis. 2001;158(1):233–239. doi:10.1016/S0021-9150(01)00423-3.
  • Shirazi-Adl A, Taheri M, Urban JP. Analysis of cell viability in intervertebral disc: effect of endplate permeability on cell population. J Biomech. 2010;43(7):1330–1336. doi:10.1016/j.jbiomech.2010.01.023.
  • Zhan JW, Wang SQ, Feng MS, Wei X, Yu J, Yin XL. Constant compression decreases vascular bud and VEGFA expression in a rabbit vertebral endplate ex vivo culture model. PLos One. 2020;15(6):e0234747. doi:10.1371/journal.pone.0234747.
  • Han IB, Ropper AE, Teng YD, Shin DA, Jeon YJ, Park HM, Shin DE, Park YS, Kim KN, Kim NK. Association between VEGF and eNOS gene polymorphisms and lumbar disc degeneration in a young Korean population. Genet Mol Res. 2013;12(3):2294–2305. doi:10.4238/2013.July.8.10.
  • Ghajar CM, George SC, Putnam AJ. Matrix metalloproteinase control of capillary morphogenesis. Crit Rev Eukaryot Gene Expr. 2008;18(3):251–278. doi:10.1615/CritRevEukarGeneExpr.v18.i3.30.
  • van Hinsbergh VW, Koolwijk P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res. 2008;78(2):203–212. doi:10.1093/cvr/cvm102.
  • Qiu S, Shi C, Anbazhagan AN, Das V, Arora V, Kc R. Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model. J Cell Physiol. 2020;235(6):5305–5317. doi:10.1002/jcp.29416.
  • Yasuma KA T, Yamauchi Y. The histology of lumbar intervertebral disc herniation. The significance of small blood vessels in the extruded tissue. Spine. 1993;18(13):1761–1765. doi:10.1097/00007632-199310000-00008.
  • Miyagi M, Uchida K, Takano S, Fujimaki H, Aikawa J, Sekiguchi H. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules in mice with intervertebral disc injury. null. 2018;36(8):2274–2279. doi:10.1002/jor.23888.
  • Moon HJ, Yurube T, Lozito TP, Pohl P, Hartman RA, Sowa GA, Kang JD, Vo NV. Effects of secreted factors in culture medium of annulus fibrosus cells on microvascular endothelial cells: elucidating the possible pathomechanisms of matrix degradation and nerve in-growth in disc degeneration. Osteoarthritis Cartilage. 2014;22(2):344–354. doi:10.1016/j.joca.2013.12.008.
  • Kwon WK, Moon HJ, Kwon TH, Park YK, Kim JH. The role of hypoxia in angiogenesis and extracellular matrix regulation of intervertebral disc cells during inflammatory reactions. Neurosurgery. 2017;81(5):867–875. doi:10.1093/neuros/nyx149.
  • Lee JM, Song JY, Baek M, Jung HY, Kang H, Han IB. Interleukin-1beta induces angiogenesis and innervation in human intervertebral disc degeneration. J Orthop Res. 2011;29(2):265–269. doi:10.1002/jor.21210.
  • Ohba T, Haro H, Ando T, Wako M, Suenaga F, Aso Y. TNF-alpha-induced NF-kappaB signaling reverses age-related declines in VEGF induction and angiogenic activity in intervertebral disc tissues. J Orthop Res. 2009;27(2):229–235. doi:10.1002/jor.20727.
  • Spiller KL, Anfang RR, Spiller KJ, Ng J, Nakazawa KR, Daulton JW. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials. 2014;35(15):4477–4488. doi:10.1016/j.biomaterials.2014.02.012.
  • Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 2014;17(1):109–118. doi:10.1007/s10456-013-9381-6.
  • Cheng X, Zhang L, Zhang K, Zhang G, Hu Y, Sun X, Zhao C, Li H, Li YM, Zhao J. Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein. Ann Rheum Dis. 2018;77(5):770–779. doi:10.1136/annrheumdis-2017-212056.
  • Xie L, Huang W, Fang Z, Ding F, Zou F, Ma X, Tao J, Guo J, Xia X, Wang H, Yu Z. CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis. Cell Death & Disease. 2019;10(10):751. doi:10.1038/s41419-019-1978-2.
  • Li Z, Chen X, Xu D, Li S, Chan MTV, Wu WKK. Circular RNAs in nucleus pulposus cell function and intervertebral disc degeneration. Cell Prolif. 2019;52(6):e12704. doi:10.1111/cpr.12704.
  • Ji ML, Jiang H, Zhang XJ, Shi PL, Li C, Wu H, Wu XT, Wang YT, Wang C, Lu J. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat Commun. 2018;9(1):5051. doi:10.1038/s41467-018-07360-1.
  • Liao Z, Luo R, Li G, Song Y, Zhan S, Zhao K. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics. 2019;9(14):4084–4100. doi:10.7150/thno.33638.
  • Zhang J, Zhang J, Zhang Y, Liu W, Ni W, Huang X. Mesenchymal stem cells-derived exosomes ameliorate intervertebral disc degeneration through inhibiting pyroptosis. J Cell Mol Med. 2020;24(20):11742–11754.
  • Lu K, Li HY, Yang K, Wu JL, Cai XW, Zhou Y. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther. 2017;8(1):108. doi:10.1186/s13287-017-0563-9.
  • Wang D, He X, Wang D, Peng P, Xu X, Gao B, Zheng C, Wang H, Jia H, Shang Q, Sun Z. Quercetin suppresses apoptosis and attenuates intervertebral disc degeneration via the SIRT1-autophagy pathway. Front Cell Dev Biol. 2020;8:613006.
  • Shao Z, Wang B, Shi Y, Xie C, Huang C, Chen B, Zhang H, Zeng G, Liang H, Wu Y, Zhou Y. Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-kappaB axis. Osteoarthritis Cartilage. 2021;29(3):413–422. doi:10.1016/j.joca.2020.11.006.
  • Novais EJ, Tran VA, Johnston SN, Darris KR, Roupas AJ, Sessions GA, Shapiro IM, Diekman BO, Risbud MV. Long-term treatment with senolytic drugs dasatinib and quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun. 2021;12(1):5213. doi:10.1038/s41467-021-25453-2.
  • Kang L, Liu S, Li J, Tian Y, Xue Y, Liu X. The mitochondria-targeted anti-oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance. Cell Prolif. 2020;53(3):e12779. doi:10.1111/cpr.12779.
  • Ge J, Cheng X, Yan Q, Wu C, Wang Y, Yu H, Yang H, Zhou F, Zou J. Calcitonin inhibits intervertebral disc degeneration by regulating protein kinase C. J Cell Mol Med. 2020;24(15):8650–8661. doi:10.1111/jcmm.15496.
  • Lin J, Zhuge J, Zheng X, Wu Y, Zhang Z, Xu T. Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway. Free Radic Biol Med. 2020;150:109–119.
  • Zhao F, Guo Z, Hou F, Fan W, Wu B, Qian Z. Magnoflorine Alleviates “M1” polarized macrophage-induced intervertebral disc degeneration through repressing the HMGB1/Myd88/NF-kappaB Pathway and NLRP3 Inflammasome. Front Pharmacol. 2021;12:701087. doi:10.3389/fphar.2021.701087.
  • Sheyn D, Ben-David S, Tawackoli W, Zhou Z, Salehi K, Bez M, De Mel, S, Chan V, Roth J, Avalos P, Giaconi JC. Human iPscs can be differentiated into notochordal cells that reduce intervertebral disc degeneration in a porcine model. Theranostics. 2019;9(25):7506–7524. doi:10.7150/thno.34898.
  • Bach FC, Tellegen AR, Beukers M, Miranda-Bedate A, Teunissen M, de Jong WAM. Biologic canine and human intervertebral disc repair by notochordal cell-derived matrix: from bench towards bedside. Oncotarget. 2018;9(41):26507–26526. doi:10.18632/oncotarget.25476.
  • de Vries S, Doeselaar MV, Meij B, Tryfonidou M, Ito K. Notochordal Cell Matrix as a Therapeutic Agent for Intervertebral Disc Regeneration. Tissue Eng Part A. 2019;25(11–12):830–841. doi:10.1089/ten.tea.2018.0026.
  • Sun Z, Liu B, Liu ZH, Song W, Wang D, Chen BY, Fan J, Xu Z, Geng D, Luo ZJ. Notochordal-Cell-derived exosomes induced by compressive load inhibit angiogenesis via the miR-140-5p/Wnt/beta-Catenin Axis. Mol Ther Nucleic Acids. 2020;22:1092–1106.
  • Stich S, Stolk M, Girod PP, Thome C, Sittinger M, Ringe J. Regenerative and immunogenic characteristics of cultured nucleus pulposus cells from human cervical intervertebral discs. PLos One. 2015;10(5):e0126954. doi:10.1371/journal.pone.0126954.
  • Acosta FL Jr., Lotz J, Ames CP. The potential role of mesenchymal stem cell therapy for intervertebral disc degeneration: a critical overview. Neurosurg Focus. 2005;19(3):E4. doi:10.3171/foc.2005.19.3.5.
  • McCann MR, Bacher CA, Seguin CA. Exploiting notochord cells for stem cell-based regeneration of the intervertebral disc. J Cell Commun Signal. 2011;5(1):39–43. doi:10.1007/s12079-010-0116-9.

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