Abstract
Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell–matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- IVD:
-
Intervertebral disc
- IVDD:
-
IVD degeneration
- AF:
-
Annulus fibrosus
- NP:
-
Nucleus pulposus
- CEP:
-
Cartilage endplate
- IAF:
-
Inner AF
- OAF:
-
Outer AF
- VB:
-
Vertebral body
- ECM:
-
Extracellular matrix
- PCM:
-
Pericellular matrix
- PG:
-
Proteoglycan
- SLRP:
-
Small leucine-rich proteoglycan
- GAG:
-
Glycosaminoglycan
- HA:
-
Hyaluronic acid
- COMP:
-
Cartilage oligomeric matrix protein
- MMP:
-
Matrix metalloproteinase
- ADAMTS:
-
A disintegrin and metalloproteinase with thrombospondin motifs
- TIMP:
-
Tissue inhibitors of metalloproteinase
References
Acharya C, Yik JH, Kishore A, Van Dinh V, Di Cesare PE, Haudenschild DR (2014) Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: interaction, regulation and role in chondrogenesis. Matrix Biol 37:102–111. https://doi.org/10.1016/j.matbio.2014.06.001
Al-Qattan MM, Al-Qattan AM (2018) Fibromodulin: structure, physiological functions, and an emphasis on its potential clinical applications in various diseases. J Coll Physicians Surg Pak 28(10):783–790
Allen KD, Griffin TM, Rodriguiz RM, Wetsel WC, Kraus VB, Huebner JL, Boyd LM, Setton LA (2009) Decreased physical function and increased pain sensitivity in mice deficient for type IX collagen. Arthritis Rheum 60(9):2684–2693. https://doi.org/10.1002/art.24783
Anderson DG, Li X, Balian G (2005) A fibronectin fragment alters the metabolism by rabbit intervertebral disc cells in vitro. Spine (Phila Pa 1976) 30(11):1242–1246. https://doi.org/10.1097/01.brs.0000164097.47091.4c
Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, Aebi M, Alini M (1996) 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 98(4):996–1003. https://doi.org/10.1172/jci118884
Aszódi A, Chan D, Hunziker E, Bateman JF, Fässler R (1998) Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol 143(5):1399–1412. https://doi.org/10.1083/jcb.143.5.1399
Attia M, Santerre JP, Kandel RA (2011) The response of annulus fibrosus cell to fibronectin-coated nanofibrous polyurethane-anionic dihydroxyoligomer scaffolds. Biomaterials 32(2):450–460. https://doi.org/10.1016/j.biomaterials.2010.09.010
Bian Q, Ma L, Jain A, Crane JL, Kebaish K, Wan M, Zhang Z, Edward Guo X, Sponseller PD, Séguin CA et al (2017) Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis. Bone Res 5:17008. https://doi.org/10.1038/boneres.2017.8
Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15(12):786–801. https://doi.org/10.1038/nrm3904
Bowles RD, Setton LA (2017) Biomaterials for intervertebral disc regeneration and repair. Biomaterials 129:54–67. https://doi.org/10.1016/j.biomaterials.2017.03.013
Boyd LM, Richardson WJ, Allen KD, Flahiff C, Jing L, Li Y, Chen J, Setton LA (2008) Early-onset degeneration of the intervertebral disc and vertebral end plate in mice deficient in type IX collagen. Arthritis Rheum 58(1):164–171. https://doi.org/10.1002/art.23231
Brayda-Bruno M, Viganò M, Cauci S, Vitale JA, de Girolamo L, De Luca P, Lombardi G, Banfi G, Colombini A (2017) Plasma vitamin D and osteo-cartilaginous markers in Italian males affected by intervertebral disc degeneration: focus on seasonal and pathological trend of type II collagen degradation. Clin Chim Acta 471:87–93. https://doi.org/10.1016/j.cca.2017.05.028
Bridgen DT, Fearing BV, Jing L, Sanchez-Adams J, Cohan MC, Guilak F, Chen J, Setton LA (2017) Regulation of human nucleus pulposus cells by peptide-coupled substrates. Acta Biomater 55:100–108. https://doi.org/10.1016/j.actbio.2017.04.019
Bridgen DT, Gilchrist CL, Richardson WJ, Isaacs RE, Brown CR, Yang KL, Chen J, Setton LA (2013) Integrin-mediated interactions with extracellular matrix proteins for nucleus pulposus cells of the human intervertebral disc. J Orthop Res 31(10):1661–1667. https://doi.org/10.1002/jor.22395
Brizzi MF, Tarone G, Defilippi P (2012) Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr Opin Cell Biol 24(5):645–651. https://doi.org/10.1016/j.ceb.2012.07.001
Brown S, Melrose J, Caterson B, Roughley P, Eisenstein SM, Roberts S (2012) A comparative evaluation of the small leucine-rich proteoglycans of pathological human intervertebral discs. Eur Spine J 21 Suppl 2(Suppl 2):S154–159. https://doi.org/10.1007/s00586-012-2179-1
Buser Z, Liu J, Thorne KJ, Coughlin D, Lotz JC (2014) Inflammatory response of intervertebral disc cells is reduced by fibrin sealant scaffold in vitro. J Tissue Eng Regen Med 8(1):77–84. https://doi.org/10.1002/term.1503
Caldeira J, Santa C, Osório H, Molinos M, Manadas B, Gonçalves R, Barbosa M (2017) Matrisome profiling during intervertebral disc development and ageing. Sci Rep 7(1):11629. https://doi.org/10.1038/s41598-017-11960-0
Chan LK, Leung VY, Tam V, Lu WW, Sze KY, Cheung KM (2013) Decellularized bovine intervertebral disc as a natural scaffold for xenogenic cell studies. Acta Biomater 9(2):5262–5272. https://doi.org/10.1016/j.actbio.2012.09.005
Chen J, Jing L, Gilchrist CL, Richardson WJ, Fitch RD, Setton LA (2009) Expression of laminin isoforms, receptors, and binding proteins unique to nucleus pulposus cells of immature intervertebral disc. Connect Tissue Res 50(5):294–306
Chen J, Mei Z, Huang B, Zhang X, Liu J, Shan Z, Wang J, Wang X, Zhao F (2019) IL-6/YAP1/β-catenin signaling is involved in intervertebral disc degeneration. J Cell Physiol 234(5):5964–5971. https://doi.org/10.1002/jcp.27065
Chen L, Liao J, Klineberg E, Leung VY, Huang S (2017) Small leucine-rich proteoglycans (SLRPs): characteristics and function in the intervertebral disc. J Tissue Eng Regen Med 11(3):602–608. https://doi.org/10.1002/term.2067
Chen RS, Zhang XB, Zhu XT, Wang CS (2020) The crosstalk between IGF-1R and ER-α in the proliferation and anti-inflammation of nucleus pulposus cells. Eur Rev Med Pharmacol Sci 24(11):5886–5894. https://doi.org/10.26355/eurrev_202006_21481
Chen S, Hu ZJ, Zhou ZJ, Lin XF, Zhao FD, Ma JJ, Zhang JF, Wang JY, Qin A, Fan SW (2015) Evaluation of 12 novel molecular markers for degenerated nucleus pulposus in a Chinese population. Spine (Phila Pa 1976) 40(16):1252–1260. https://doi.org/10.1097/brs.0000000000000929
Chik TK, Chooi WH, Li YY, Ho FC, Cheng HW, Choy TH, Sze KY, Luk KK, Cheung KM, Chan BP (2015) Bioengineering a multicomponent spinal motion segment construct–a 3D model for complex tissue engineering. Adv Healthc Mater 4(1):99–112. https://doi.org/10.1002/adhm.201400192
Choy AT, Chan BP (2015) A structurally and functionally biomimetic biphasic scaffold for intervertebral disc tissue engineering. PLoS ONE 10(6):e0131827. https://doi.org/10.1371/journal.pone.0131827
Cloyd JM, Elliott DM (2007) Elastin content correlates with human disc degeneration in the anulus fibrosus and nucleus pulposus. Spine (Phila Pa 1976) 32(17):1826–1831. https://doi.org/10.1097/BRS.0b013e3181132a9d
Cohen SP (2015) Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc 90(2):284–299. https://doi.org/10.1016/j.mayocp.2014.09.008
Collin EC, Grad S, Zeugolis DI, Vinatier CS, Clouet JR, Guicheux JJ, Weiss P, Alini M, Pandit AS (2011) An injectable vehicle for nucleus pulposus cell-based therapy. Biomaterials 32(11):2862–2870. https://doi.org/10.1016/j.biomaterials.2011.01.018
Csapo R, Gumpenberger M, Wessner B (2020) Skeletal muscle extracellular matrix - what do we know about its composition, regulation, and physiological roles? A Narrative Review Front Physiol 11:253. https://doi.org/10.3389/fphys.2020.00253
Cuellar JM, Golish SR, Leroux EJ, Reuter MW, Carragee EJ, Hanna LS, Scuderi GJ (2013) Does a fibronectin and aggrecan complex play a role in painful vertebral disks? PM&R 5(4):297–302; quiz 302. https://doi.org/10.1016/j.pmrj.2013.01.002
Cui M, Wan Y, Anderson DG, Shen FH, Leo BM, Laurencin CT, Balian G, Li X (2008) Mouse growth and differentiation factor-5 protein and DNA therapy potentiates intervertebral disc cell aggregation and chondrogenic gene expression. Spine J 8(2):287–295. https://doi.org/10.1016/j.spinee.2007.05.012
DeLucca JF, Cortes DH, Jacobs NT, Vresilovic EJ, Duncan RL, Elliott DM (2016) Human cartilage endplate permeability varies with degeneration and intervertebral disc site. J Biomech 49(4):550–557. https://doi.org/10.1016/j.jbiomech.2016.01.007
Dondossola E, Holzapfel BM, Alexander S, Filippini S, Hutmacher DW, Friedl P (2016) Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat Biomed Eng 1. https://doi.org/10.1038/s41551-016-0007
Duncan NA (2006) Cell deformation and micromechanical environment in the intervertebral disc. J Bone Joint Surg Am 88(Suppl 2):47–51. https://doi.org/10.2106/jbjs.f.00035
Eyre DR, Wu JJ, Fernandes RJ, Pietka TA, Weis MA (2002) Recent developments in cartilage research: matrix biology of the collagen II/IX/XI heterofibril network. Biochem Soc Trans 30(Pt 6):893–899. https://doi.org/10.1042/bst0300893
Fearing BV, Jing L, Barcellona MN, Witte SE, Buchowski JM, Zebala LP, Kelly MP, Luhmann S, Gupta MC, Pathak A et al (2019) Mechanosensitive transcriptional coactivators MRTF-A and YAP/TAZ regulate nucleus pulposus cell phenotype through cell shape. Faseb J 33(12):14022–14035. https://doi.org/10.1096/fj.201802725RRR
Fei QM, Jiang XX, Chen TY, Li J, Murakami H, Tsai KJ, Hutton WC (2006) Changes with age and the effect of recombinant human BMP-2 on proteoglycan and collagen gene expression in rabbit anulus fibrosus cells. Acta Biochim Biophys Sin (shanghai) 38(11):773–779. https://doi.org/10.1111/j.1745-7270.2006.00230.x
Feldman N, Rotter-Maskowitz A, Okun E (2015) DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 24(Pt A):29–39. https://doi.org/10.1016/j.arr.2015.01.003
Feng C, He J, Zhang Y, Lan M, Yang M, Liu H, Huang B, Pan Y, Zhou Y (2017a) Collagen-derived N-acetylated proline-glycine-proline upregulates the expression of pro-inflammatory cytokines and extracellular matrix proteases in nucleus pulposus cells via the NF-κB and MAPK signaling pathways. Int J Mol Med 40(1):164–174. https://doi.org/10.3892/ijmm.2017.3005
Feng C, Liu H, Yang M, Zhang Y, Huang B, Zhou Y (2016) Disc cell senescence in intervertebral disc degeneration: causes and molecular pathways. Cell Cycle 15(13):1674–1684. https://doi.org/10.1080/15384101.2016.1152433
Feng C, Yang M, Lan M, Liu C, Zhang Y, Huang B, Liu H, Zhou Y (2017b) ROS: crucial intermediators in the pathogenesis of intervertebral disc degeneration. Oxid Med Cell Longev 2017:5601593. https://doi.org/10.1155/2017/5601593
Feng C, Zhang Y, Yang M, Huang B, Zhou Y (2015) Collagen-derived N-acetylated proline-glycine-proline in intervertebral discs modulates CXCR1/2 expression and activation in cartilage endplate stem cells to induce migration and differentiation toward a pro-inflammatory phenotype. Stem Cells 33(12):3558–3568. https://doi.org/10.1002/stem.2200
Feng C, Zhang Y, Yang M, Lan M, Liu H, Wang J, Zhou Y, Huang B (2017c) The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs. Biochim Biophys Acta Mol Basis Dis 1863(1):220–230. https://doi.org/10.1016/j.bbadis.2016.10.011
Fiordalisi M, Silva AJ, Barbosa M, Gonçalves R, Caldeira J (2020) Decellularized scaffolds for intervertebral disc regeneration. Trends Biotechnol. https://doi.org/10.1016/j.tibtech.2020.05.002
Foldager CB, Toh WS, Gomoll AH, Olsen BR, Spector M (2014) Distribution of basement membrane molecules, laminin and collagen type IV, in normal and degenerated cartilage tissues. Cartilage 5(2):123–132. https://doi.org/10.1177/1947603513518217
Fontes RBV, Baptista JS, Rabbani SR, Traynelis VC, Liberti EA (2019) Normal aging in human lumbar discs: an ultrastructural comparison. PLoS ONE 14(6):e0218121. https://doi.org/10.1371/journal.pone.0218121
Francisco AT, Mancino RJ, Bowles RD, Brunger JM, Tainter DM, Chen YT, Richardson WJ, Guilak F, Setton LA (2013) Injectable laminin-functionalized hydrogel for nucleus pulposus regeneration. Biomaterials 34(30):7381–7388. https://doi.org/10.1016/j.biomaterials.2013.06.038
Furukawa T, Ito K, Nuka S, Hashimoto J, Takei H, Takahara M, Ogino T, Young MF, Shinomura T (2009) Absence of biglycan accelerates the degenerative process in mouse intervertebral disc. Spine (Phila Pa 1976) 34(25):E911–917. https://doi.org/10.1097/BRS.0b013e3181b7c7ec
Götz W, Barnert S, Bertagnoli R, Miosge N, Kresse H, Herken R (1997) Immunohistochemical localization of the small proteoglycans decorin and biglycan in human intervertebral discs. Cell Tissue Res 289(1):185–190. https://doi.org/10.1007/s004410050864
Gaggar A, Jackson PL, Noerager BD, O’Reilly PJ, McQuaid DB, Rowe SM, Clancy JP, Blalock JE (2008) A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol 180(8):5662–5669. https://doi.org/10.4049/jimmunol.180.8.5662
Galbusera F, van Rijsbergen M, Ito K, Huyghe JM, Brayda-Bruno M, Wilke HJ (2014) Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility. Eur Spine J 23(Suppl 3):S324-332. https://doi.org/10.1007/s00586-014-3203-4
Garnero P, Sornay-Rendu E, Arlot M, Christiansen C, Delmas PD (2004) Association between spine disc degeneration and type II collagen degradation in postmenopausal women: the OFELY study. Arthritis Rheum 50(10):3137–3144. https://doi.org/10.1002/art.20493
Ge J, Yan Q, Wang Y, Cheng X, Song D, Wu C, Yu H, Yang H, Zou J (2020) IL-10 delays the degeneration of intervertebral discs by suppressing the p38 MAPK signaling pathway. Free Radic Biol Med 147:262–270. https://doi.org/10.1016/j.freeradbiomed.2019.12.040
Gilbert HT, Nagra NS, Freemont AJ, Millward-Sadler SJ, Hoyland JA (2013) Integrin - dependent mechanotransduction in mechanically stimulated human annulus fibrosus cells: evidence for an alternative mechanotransduction pathway operating with degeneration. PLoS ONE 8(9):e72994. https://doi.org/10.1371/journal.pone.0072994
Gilbertson L, Ahn SH, Teng PN, Studer RK, Niyibizi C, Kang JD (2008) The effects of recombinant human bone morphogenetic protein-2, recombinant human bone morphogenetic protein-12, and adenoviral bone morphogenetic protein-12 on matrix synthesis in human annulus fibrosis and nucleus pulposus cells. Spine J 8(3):449–456. https://doi.org/10.1016/j.spinee.2006.11.006
Gilchrist CL, Chen J, Richardson WJ, Loeser RF, Setton LA (2007) Functional integrin subunits regulating cell-matrix interactions in the intervertebral disc. J Orthop Res 25(6):829–840. https://doi.org/10.1002/jor.20343
Gilchrist CL, Francisco AT, Plopper GE, Chen J, Setton LA (2011) Nucleus pulposus cell-matrix interactions with laminins. Eur Cell Mater 21:523–532. https://doi.org/10.22203/ecm.v021a39
Gorth DJ, Ottone OK, Shapiro IM, Risbud MV (2020) Differential effect of long-term systemic exposure of TNFα on health of the annulus fibrosus and nucleus pulposus of the intervertebral disc. J Bone Miner Res 35(4):725–737. https://doi.org/10.1002/jbmr.3931
Gorth DJ, Shapiro IM, Risbud MV (2018) Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration. Cell Death Dis 10(1):7. https://doi.org/10.1038/s41419-018-1246-x
Greg Anderson D, Li X, Tannoury T, Beck G, Balian G (2003) A fibronectin fragment stimulates intervertebral disc degeneration in vivo. Spine (Phila Pa 1976) 28(20):2338–2345. https://doi.org/10.1097/01.brs.0000096943.27853.bc
Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Zinchenko N, Hanley EN Jr (2011) Variations in aggrecan localization and gene expression patterns characterize increasing stages of human intervertebral disk degeneration. Exp Mol Pathol 91(2):534–539. https://doi.org/10.1016/j.yexmp.2011.06.001
Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Hanley EN Jr, Sun Y (2009) Asporin, a susceptibility gene in osteoarthritis, is expressed at higher levels in the more degenerate human intervertebral disc. Arthritis Res Ther 11(2):R47. https://doi.org/10.1186/ar2660
Gruber HE, Ingram JA, Norton HJ, Hanley EN Jr (2007) Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence-associated beta-galactosidase in human and sand rat discs. Spine (Phila Pa 1976) 32(3):321–327. https://doi.org/10.1097/01.brs.0000253960.57051.de
Guerrero J, Häckel S, Croft AS, Hoppe S, Albers CE, Gantenbein B (2021) The nucleus pulposus microenvironment in the intervertebral disc: the fountain of youth? Eur Cell Mater 41:707–738. https://doi.org/10.22203/eCM.v041a46
Halloran DO, Grad S, Stoddart M, Dockery P, Alini M, Pandit AS (2008) An injectable cross-linked scaffold for nucleus pulposus regeneration. Biomaterials 29(4):438–447. https://doi.org/10.1016/j.biomaterials.2007.10.009
Hartvigsen J, Hancock MJ, Kongsted A, Louw Q, Ferreira ML, Genevay S, Hoy D, Karppinen J, Pransky G, Sieper J et al (2018) What low back pain is and why we need to pay attention. Lancet 391(10137):2356–2367. https://doi.org/10.1016/s0140-6736(18)30480-x
Hayes AJ, Benjamin M, Ralphs JR (1999) Role of actin stress fibres in the development of the intervertebral disc: cytoskeletal control of extracellular matrix assembly. Dev Dyn 215(3):179–189. https://doi.org/10.1002/(sici)1097-0177(199907)215:3%3c179::aid-aja1%3e3.0.co;2-q
Hayes AJ, Benjamin M, Ralphs JR (2001) Extracellular matrix in development of the intervertebral disc. Matrix Biol 20(2):107–121. https://doi.org/10.1016/s0945-053x(01)00125-1
Hayes AJ, Isaacs MD, Hughes C, Caterson B, Ralphs JR (2011a) Collagen fibrillogenesis in the development of the annulus fibrosus of the intervertebral disc. Eur Cell Mater 22:226–241. https://doi.org/10.22203/ecm.v022a18
Hayes AJ, Lord MS, Smith SM, Smith MM, Whitelock JM, Weiss AS, Melrose J (2011b) Colocalization in vivo and association in vitro of perlecan and elastin. Histochem Cell Biol 136(4):437–454. https://doi.org/10.1007/s00418-011-0854-7
Hayes AJ, Melrose J (2021) 3D distribution of perlecan within intervertebral disc chondrons suggests novel regulatory roles for this multifunctional modular heparan sulphate proteoglycan. Eur Cell Mater 41:73–89. https://doi.org/10.22203/eCM.v041a06
Hayes AJ, Shu CC, Lord MS, Little CB, Whitelock JM, Melrose J (2016) Pericellular colocalisation and interactive properties of type VI collagen and perlecan in the intervertebral disc. Eur Cell Mater 32:40–57. https://doi.org/10.22203/ecm.v032a03
Hayes AJ, Smith SM, Gibson MA, Melrose J (2011c) Comparative immunolocalization of the elastin fiber-associated proteins fibrillin-1, LTBP-2, and MAGP-1 with components of the collagenous and proteoglycan matrix of the fetal human intervertebral disc. Spine (Phila Pa 1976) 36(21):E1365–1372. https://doi.org/10.1097/BRS.0b013e31821fd23e
Hegewald AA, Zouhair S, Endres M, Cabraja M, Woiciechowsky C, Thomé C, Kaps C (2013) Towards biological anulus repair: TGF-β3, FGF-2 and human serum support matrix formation by human anulus fibrosus cells. Tissue Cell 45(1):68–76. https://doi.org/10.1016/j.tice.2012.09.011
Hensley A, Rames J, Casler V, Rood C, Walters J, Fernandez C, Gill S, Mercuri JJ (2018) Decellularization and characterization of a whole intervertebral disk xenograft scaffold. J Biomed Mater Res A 106(9):2412–2423. https://doi.org/10.1002/jbm.a.36434
Hodgkinson T, Gilbert HTJ, Pandya T, Diwan AD, Hoyland JA, Richardson SM (2020) Regenerative response of degenerate human nucleus pulposus cells to GDF6 stimulation. Int J Mol Sci 21(19). https://doi.org/10.3390/ijms21197143
Hofmann UK, Steidle J, Danalache M, Bonnaire F, Walter C, Rolauffs B (2018) Chondrocyte death after mechanically overloading degenerated human intervertebral disk explants is associated with a structurally impaired pericellular matrix. J Tissue Eng Regen Med 12(9):2000–2010. https://doi.org/10.1002/term.2735
Hondke S, Cabraja M, Krüger JP, Stich S, Hartwig T, Sittinger M, Endres M (2020) Proliferation, migration, and ECM formation potential of human annulus fibrosus cells is independent of degeneration status. Cartilage 11(2):192–202. https://doi.org/10.1177/1947603518764265
Huang JF, Zheng XQ, Lin JL, Zhang K, Tian HJ, Zhou WX, Wang H, Gao Z, Jin HM, Wu AM (2020) Sinapic acid inhibits IL-1β-induced apoptosis and catabolism in nucleus pulposus cells and ameliorates intervertebral disk degeneration. J Inflamm Res 13:883–895. https://doi.org/10.2147/jir.s278556
Huang KY, Lin RM, Chen WY, Lee CL, Yan JJ, Chang MS (2008) IL-20 may contribute to the pathogenesis of human intervertebral disc herniation. Spine (Phila Pa 1976) 33(19):2034–2040. https://doi.org/10.1097/BRS.0b013e31817eb872
Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326(5957):1216–1219. https://doi.org/10.1126/science.1176009
Iatridis JC, Nicoll SB, Michalek AJ, Walter BA, Gupta MS (2013) 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 13(3):243–262. https://doi.org/10.1016/j.spinee.2012.12.002
Ikegawa S (2008) Expression, regulation and function of asporin, a susceptibility gene in common bone and joint diseases. Curr Med Chem 15(7):724–728. https://doi.org/10.2174/092986708783885237
Illien-Jünger S, Sedaghatpour DD, Laudier DM, Hecht AC, Qureshi SA, Iatridis JC (2016) Development of a bovine decellularized extracellular matrix-biomaterial for nucleus pulposus regeneration. J Orthop Res 34(5):876–888. https://doi.org/10.1002/jor.23088
Inkinen RI, Lammi MJ, Agren U, Tammi R, Puustjarvi K, Tammi MI (1999) Hyaluronan distribution in the human and canine intervertebral disc and cartilage endplate. Histochem J 31(9):579–587. https://doi.org/10.1023/a:1003898923823
Inkinen RI, Lammi MJ, Lehmonen S, Puustjärvi K, Kääpä E, Tammi MI (1998) Relative increase of biglycan and decorin and altered chondroitin sulfate epitopes in the degenerating human intervertebral disc. J Rheumatol 25(3):506–514
Ishii Y, Thomas AO, Guo XE, Hung CT, Chen FH (2006) Localization and distribution of cartilage oligomeric matrix protein in the rat intervertebral disc. Spine (Phila Pa 1976) 31(14):1539–1546. https://doi.org/10.1097/01.brs.0000221994.61882.4a
Johnson MS, Lu N, Denessiouk K, Heino J, Gullberg D (2009) Integrins during evolution: evolutionary trees and model organisms. Biochim Biophys Acta 1788(4):779–789. https://doi.org/10.1016/j.bbamem.2008.12.013
Johnson WE, Caterson B, Eisenstein SM, Hynds DL, Snow DM, Roberts S (2002) Human intervertebral disc aggrecan inhibits nerve growth in vitro. Arthritis Rheum 46(10):2658–2664. https://doi.org/10.1002/art.10585
Johnson WE, Caterson B, Eisenstein SM, Roberts S (2005) Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro. Spine (Phila Pa 1976) 30(10):1139–1147. https://doi.org/10.1097/01.brs.0000162624.95262.73
Johnstone B, Markopoulos M, Neame P, Caterson B (1993) Identification and characterization of glycanated and non-glycanated forms of biglycan and decorin in the human intervertebral disc. Biochem J 292 ( Pt 3)(Pt 3):661–666. https://doi.org/10.1042/bj2920661
Kääpä E, Han X, Holm S, Peltonen J, Takala T, Vanharanta H (1995) Collagen synthesis and types I, III, IV, and VI collagens in an animal model of disc degeneration. Spine (Phila Pa 1976) 20(1):59–66; discussion 66–57. https://doi.org/10.1097/00007632-199501000-00011
Kanda Y, Yurube T, Morita Y, Takeoka Y, Kurakawa T, Tsujimoto R, Miyazaki K, Kakiuchi Y, Miyazaki S, Zhang Z et al (2021) Delayed notochordal cell disappearance through integrin α5β1 mechanotransduction during ex-vivo dynamic loading-induced intervertebral disc degeneration. J Orthop Res 39(9):1933–1944. https://doi.org/10.1002/jor.24883
Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276(16):12501–12504. https://doi.org/10.1074/jbc.C000848200
Kim JS, Ellman MB, An HS, van Wijnen AJ, Borgia JA, Im HJ (2010) Insulin-like growth factor 1 synergizes with bone morphogenetic protein 7-mediated anabolism in bovine intervertebral disc cells. Arthritis Rheum 62(12):3706–3715. https://doi.org/10.1002/art.27733
Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi A, Kotani A, Kawakami A, Yamamoto S et al (2005) An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 37(2):138–144. https://doi.org/10.1038/ng1496
Kobielarz M, Szotek S, Głowacki M, Dawidowicz J, Pezowicz C (2016) Qualitative and quantitative assessment of collagen and elastin in annulus fibrosus of the physiologic and scoliotic intervertebral discs. J Mech Behav Biomed Mater 62:45–56. https://doi.org/10.1016/j.jmbbm.2016.04.033
Krock E, Rosenzweig DH, Currie JB, Bisson DG, Ouellet JA, Haglund L (2017) Toll-like receptor activation induces degeneration of human intervertebral discs. Sci Rep 7(1):17184. https://doi.org/10.1038/s41598-017-17472-1
Krouwels A, Iljas JD, Kragten AHM, Dhert WJA, Öner FC, Tryfonidou MA, Creemers LB (2020) Bone morphogenetic proteins for nucleus pulposus regeneration. Int J Mol Sci 21(8). https://doi.org/10.3390/ijms21082720
Kuh SU, Zhu Y, Li J, Tsai KJ, Fei Q, Hutton WC, Yoon TS (2009) A comparison of three cell types as potential candidates for intervertebral disc therapy: annulus fibrosus cells, chondrocytes, and bone marrow derived cells. Joint Bone Spine 76(1):70–74. https://doi.org/10.1016/j.jbspin.2008.02.021
Kurakawa T, Kakutani K, Morita Y, Kato Y, Yurube T, Hirata H, Miyazaki S, Terashima Y, Maeno K, Takada T et al (2015) Functional impact of integrin α5β1 on the homeostasis of intervertebral discs: a study of mechanotransduction pathways using a novel dynamic loading organ culture system. Spine J 15(3):417–426. https://doi.org/10.1016/j.spinee.2014.12.143
Lama P, Claireaux H, Flower L, Harding IJ, Dolan T, Le Maitre CL, Adams MA (2019) Physical disruption of intervertebral disc promotes cell clustering and a degenerative phenotype. Cell Death Discov 5:154. https://doi.org/10.1038/s41420-019-0233-z
Le Maitre CL, Frain J, Millward-Sadler J, Fotheringham AP, Freemont AJ, Hoyland JA (2009a) Altered integrin mechanotransduction in human nucleus pulposus cells derived from degenerated discs. Arthritis Rheum 60(2):460–469. https://doi.org/10.1002/art.24248
Le Maitre CL, Freemont AJ, Hoyland JA (2007) Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther 9(3):R45. https://doi.org/10.1186/ar2198
Le Maitre CL, Freemont AJ, Hoyland JA (2009b) Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells. Arthritis Res Ther 11(5):R137. https://doi.org/10.1186/ar2808
Li B, Urban JP, Yu J (2012) The distribution of fibrillin-2 and LTBP-2, and their co-localisation with fibrillin-1 in adult bovine tail disc. J Anat 220(2):164–172. https://doi.org/10.1111/j.1469-7580.2011.01455.x
Li B, Zheng XF, Ni BB, Yang YH, Jiang SD, Lu H, Jiang LS (2013) Reduced expression of insulin-like growth factor 1 receptor leads to accelerated intervertebral disc degeneration in mice. Int J Immunopathol Pharmacol 26(2):337–347. https://doi.org/10.1177/039463201302600207
Li J, Yoon ST, Hutton WC (2004a) Effect of bone morphogenetic protein-2 (BMP-2) on matrix production, other BMPs, and BMP receptors in rat intervertebral disc cells. J Spinal Disord Tech 17(5):423–428. https://doi.org/10.1097/01.bsd.0000112084.85112.5d
Li J, Yuan W, Jiang S, Ye W, Yang H, Shapiro IM, Risbud MV (2015) Prolyl-4-hydroxylase domain protein 2 controls NF-κB/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus. J Biol Chem 290(11):7195–7207. https://doi.org/10.1074/jbc.M114.611483
Li K, Kapper D, Youngs B, Kocsis V, Mondal S, Kraus P, Lufkin T (2019) Potential biomarkers of the mature intervertebral disc identified at the single cell level. J Anat 234(1):16–32. https://doi.org/10.1111/joa.12904
Li P, Gan Y, Xu Y, Song L, Wang L, Ouyang B, Zhang C, Zhou Q (2017) The inflammatory cytokine TNF-α promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway. Sci Rep 7:42938. https://doi.org/10.1038/srep42938
Li X, An HS, Ellman M, Phillips F, Thonar EJ, Park DK, Udayakumar RK, Im HJ (2008) Action of fibroblast growth factor-2 on the intervertebral disc. Arthritis Res Ther 10(2):R48. https://doi.org/10.1186/ar2407
Li X, Leo BM, Beck G, Balian G, Anderson GD (2004b) Collagen and proteoglycan abnormalities in the GDF-5-deficient mice and molecular changes when treating disk cells with recombinant growth factor. Spine (Phila Pa 1976) 29(20):2229–2234. https://doi.org/10.1097/01.brs.0000142427.82605.fb
Li Y, Zhang T, Tian W, Hu H, Xin Z, Ma X, Ye C, Hang K, Han X, Zhao J et al (2020) Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: a new mechanism of intervertebral disc degeneration. Faseb J 34(4):5483–5498. https://doi.org/10.1096/fj.201902364RR
Lin D, Alberton P, Delgado Caceres M, Prein C, Clausen-Schaumann H, Dong J, Aszodi A, Shukunami C, Iatridis JC, Docheva D (2020) Loss of tenomodulin expression is a risk factor for age-related intervertebral disc degeneration. Aging Cell 19(3):e13091. https://doi.org/10.1111/acel.13091
Lin J, Chen J, Zhang Z, Xu T, Shao Z, Wang X, Ding Y, Tian N, Jin H, Sheng S et al (2019) Luteoloside inhibits IL-1β-induced apoptosis and catabolism in nucleus pulposus cells and ameliorates intervertebral disk degeneration. Front Pharmacol 10:868. https://doi.org/10.3389/fphar.2019.00868
Liu HF, Zhang H, Qiao GX, Ning B, Hu YL, Wang DC, Hu YG (2013) A novel rabbit disc degeneration model induced by fibronectin fragment. Joint Bone Spine 80(3):301–306. https://doi.org/10.1016/j.jbspin.2012.07.009
Liu J, Wei X, Huang B, Wu H, Zhang X, Chen J, Shan Z, Fan S, Zhao F (2020) Lubricin expression in the lumbar endplate and its association with Modic changes. J Orthop Translat 22:124–131. https://doi.org/10.1016/j.jot.2019.10.009
Loeser RF (2014) Integrins and chondrocyte-matrix interactions in articular cartilage. Matrix Biol 39:11–16. https://doi.org/10.1016/j.matbio.2014.08.007
Ludwinski FE, Gnanalingham K, Richardson SM, Hoyland JA (2013) Understanding the native nucleus pulposus cell phenotype has important implications for intervertebral disc regeneration strategies. Regen Med 8(1):75–87. https://doi.org/10.2217/rme.12.108
Macri L, Silverstein D, Clark RA (2007) Growth factor binding to the pericellular matrix and its importance in tissue engineering. Adv Drug Deliv Rev 59(13):1366–1381. https://doi.org/10.1016/j.addr.2007.08.015
Malandrino A, Lacroix D, Hellmich C, Ito K, Ferguson SJ, Noailly J (2014) The role of endplate poromechanical properties on the nutrient availability in the intervertebral disc. Osteoarthritis Cartilage 22(7):1053–1060. https://doi.org/10.1016/j.joca.2014.05.005
Marchand F, Ahmed AM (1990) Investigation of the laminate structure of lumbar disc anulus fibrosus. Spine (Phila Pa 1976) 15(5):402–410. https://doi.org/10.1097/00007632-199005000-00011
McKee TJ, Perlman G, Morris M, Komarova SV (2019) Extracellular matrix composition of connective tissues: a systematic review and meta-analysis. Sci Rep 9(1):10542. https://doi.org/10.1038/s41598-019-46896-0
Melrose J, Ghosh P, Taylor TK (2001) A comparative analysis of the differential spatial and temporal distributions of the large (aggrecan, versican) and small (decorin, biglycan, fibromodulin) proteoglycans of the intervertebral disc. J Anat 198(Pt 1):3–15. https://doi.org/10.1046/j.1469-7580.2001.19810003.x
Melrose J, Hayes AJ, Whitelock JM, Little CB (2008a) Perlecan, the “jack of all trades” proteoglycan of cartilaginous weight-bearing connective tissues. BioEssays 30(5):457–469. https://doi.org/10.1002/bies.20748
Melrose J, Smith SM, Appleyard RC, Little CB (2008b) Aggrecan, versican and type VI collagen are components of annular translamellar crossbridges in the intervertebral disc. Eur Spine J 17(2):314–324. https://doi.org/10.1007/s00586-007-0538-0
Melrose J, Smith SM, Fuller ES, Young AA, Roughley PJ, Dart A, Little CB (2007) Biglycan and fibromodulin fragmentation correlates with temporal and spatial annular remodelling in experimentally injured ovine intervertebral discs. Eur Spine J 16(12):2193–2205. https://doi.org/10.1007/s00586-007-0497-5
Melrose J, Tammi M, Smith S (2002) Visualisation of hyaluronan and hyaluronan-binding proteins within ovine vertebral cartilages using biotinylated aggrecan G1-link complex and biotinylated hyaluronan oligosaccharides. Histochem Cell Biol 117(4):327–333. https://doi.org/10.1007/s00418-002-0392-4
Michalek AJ, Buckley MR, Bonassar LJ, Cohen I, Iatridis JC (2009) Measurement of local strains in intervertebral disc anulus fibrosus tissue under dynamic shear: contributions of matrix fiber orientation and elastin content. J Biomech 42(14):2279–2285. https://doi.org/10.1016/j.jbiomech.2009.06.047
Molinos M, Almeida CR, Caldeira J, Cunha C, Goncalves RM, Barbosa MA (2015) Inflammation in intervertebral disc degeneration and regeneration. J R Soc Interface 12(104):20141191. https://doi.org/10.1098/rsif.2014.1191
Molinos M, Cunha C, Almeida CR, Gonçalves RM, Pereira P, Silva PS, Vaz R, Barbosa MA (2018) Age-correlated phenotypic alterations in cells isolated from human degenerated intervertebral discs with contained hernias. Spine (Phila Pa 1976) 43(5):E274-e284. https://doi.org/10.1097/brs.0000000000002311
Murshed M (2018) Mechanism of bone mineralization. Cold Spring Harb Perspect Med 8(12). https://doi.org/10.1101/cshperspect.a031229
Nakajima M, Kizawa H, Saitoh M, Kou I, Miyazono K, Ikegawa S (2007) Mechanisms for asporin function and regulation in articular cartilage. J Biol Chem 282(44):32185–32192. https://doi.org/10.1074/jbc.M700522200
Nasto LA, Robinson AR, Ngo K, Clauson CL, Dong Q, St Croix C, Sowa G, Pola E, Robbins PD, Kang J et al (2013) Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration. J Orthop Res 31(7):1150–1157. https://doi.org/10.1002/jor.22320
Nerlich AG, Schleicher ED, Boos N (1997) 1997 Volvo Award winner in basic science studies. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976) 22(24):2781–2795. https://doi.org/10.1097/00007632-199712150-00001
Newell N, Little JP, Christou A, Adams MA, Adam CJ, Masouros SD (2017) Biomechanics of the human intervertebral disc: a review of testing techniques and results. J Mech Behav Biomed Mater 69:420–434. https://doi.org/10.1016/j.jmbbm.2017.01.037
Novais EJ, Tran VA, Johnston SN, Darris KR, Roupas AJ, Sessions GA, Shapiro IM, Diekman BO, Risbud MV (2021) Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun 12(1):5213. https://doi.org/10.1038/s41467-021-25453-2
Paietta RC, Burger EL, Ferguson VL (2013) Mineralization and collagen orientation throughout aging at the vertebral endplate in the human lumbar spine. J Struct Biol 184(2):310–320. https://doi.org/10.1016/j.jsb.2013.08.011
Patel KP, Sandy JD, Akeda K, Miyamoto K, Chujo T, An HS, Masuda K (2007) Aggrecanases and aggrecanase-generated fragments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine (Phila Pa 1976) 32(23):2596–2603. https://doi.org/10.1097/BRS.0b013e318158cb85
Patil P, Dong Q, Wang D, Chang J, Wiley C, Demaria M, Lee J, Kang J, Niedernhofer LJ, Robbins PD et al (2019) Systemic clearance of p16(INK4a) -positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell 18(3):e12927. https://doi.org/10.1111/acel.12927
Pearce RH, Mathieson JM, Mort JS, Roughley PJ (1989) Effect of age on the abundance and fragmentation of link protein of the human intervertebral disc. J Orthop Res 7(6):861–867. https://doi.org/10.1002/jor.1100070612
Peng Y, Huang D, Liu S, Li J, Qing X, Shao Z (2020) Biomaterials-induced stem cells specific differentiation into intervertebral disc lineage cells. Front Bioeng Biotechnol 8:56. https://doi.org/10.3389/fbioe.2020.00056
Peng Y, Qing X, Lin H, Huang D, Li J, Tian S, Liu S, Lv X, Ma K, Li R et al (2021a) Decellularized Disc Hydrogels for hBMSCs tissue-specific differentiation and tissue regeneration. Bioact Mater 6(10):3541–3556. https://doi.org/10.1016/j.bioactmat.2021.03.014
Peng Z, Sun H, Bunpetch V, Koh Y, Wen Y, Wu D, Ouyang H (2021b) The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials 268:120555. https://doi.org/10.1016/j.biomaterials.2020.120555
Phillips KL, Jordan-Mahy N, Nicklin MJ, Le Maitre CL (2013) Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann Rheum Dis 72(11):1860–1867. https://doi.org/10.1136/annrheumdis-2012-202266
Pockert AJ, Richardson SM, Le Maitre CL, Lyon M, Deakin JA, Buttle DJ, Freemont AJ, Hoyland JA (2009) Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum 60(2):482–491. https://doi.org/10.1002/art.24291
Quero L, Klawitter M, Schmaus A, Rothley M, Sleeman J, Tiaden AN, Klasen J, Boos N, Hottiger MO, Wuertz K et al (2013) Hyaluronic acid fragments enhance the inflammatory and catabolic response in human intervertebral disc cells through modulation of toll-like receptor 2 signalling pathways. Arthritis Res Ther 15(4):R94. https://doi.org/10.1186/ar4274
Razaq S, Wilkins RJ, Urban JP (2003) The effect of extracellular pH on matrix turnover by cells of the bovine nucleus pulposus. Eur Spine J 12(4):341–349. https://doi.org/10.1007/s00586-003-0582-3
Ricard-Blum S (2011) The collagen family. Cold Spring Harb Perspect Biol 3(1):a004978. https://doi.org/10.1101/cshperspect.a004978
Rodriguez E, Roughley P (2006) Link protein can retard the degradation of hyaluronan in proteoglycan aggregates. Osteoarthritis Cartilage 14(8):823–829. https://doi.org/10.1016/j.joca.2006.02.008
Roughley PJ, Lamplugh L, Lee ER, Matsumoto K, Yamaguchi Y (2011) The role of hyaluronan produced by Has2 gene expression in development of the spine. Spine (Phila Pa 1976) 36(14):E914–920. https://doi.org/10.1097/BRS.0b013e3181f1e84f
Roughley PJ, Melching LI, Heathfield TF, Pearce RH, Mort JS (2006) The structure and degradation of aggrecan in human intervertebral disc. Eur Spine J 15 Suppl 3(Suppl 3):S326–332. https://doi.org/10.1007/s00586-006-0127-7
Ruel N, Markova DZ, Adams SL, Scanzello C, Cs-Szabo G, Gerard D, Shi P, Anderson DG, Zack M, An HS et al (2014) Fibronectin fragments and the cleaving enzyme ADAM-8 in the degenerative human intervertebral disc. Spine (Phila Pa 1976) 39(16):1274–1279. https://doi.org/10.1097/brs.0000000000000397
Rutges JP, Duit RA, Kummer JA, Bekkers JE, Oner FC, Castelein RM, Dhert WJ, Creemers LB (2013) A validated new histological classification for intervertebral disc degeneration. Osteoarthritis Cartilage 21(12):2039–2047. https://doi.org/10.1016/j.joca.2013.10.001
Sahlman J, Inkinen R, Hirvonen T, Lammi MJ, Lammi PE, Nieminen J, Lapveteläinen T, Prockop DJ, Arita M, Li SW et al (2001) Premature vertebral endplate ossification and mild disc degeneration in mice after inactivation of one allele belonging to the Col2a1 gene for type II collagen. Spine (Phila Pa 1976) 26(23):2558–2565. https://doi.org/10.1097/00007632-200112010-00008
Sakai D, Grad S (2015) Advancing the cellular and molecular therapy for intervertebral disc disease. Adv Drug Deliv Rev 84:159–171. https://doi.org/10.1016/j.addr.2014.06.009
Sarver JJ, Elliott DM (2004) Altered disc mechanics in mice genetically engineered for reduced type I collagen. Spine (Phila Pa 1976) 29(10):1094–1098. https://doi.org/10.1097/00007632-200405150-00009
Schwartz MA (2010) Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb Perspect Biol 2(12):a005066. https://doi.org/10.1101/cshperspect.a005066
Sharifi S, van Kooten TG, Kranenburg HJ, Meij BP, Behl M, Lendlein A, Grijpma DW (2013) An annulus fibrosus closure device based on a biodegradable shape-memory polymer network. Biomaterials 34(33):8105–8113. https://doi.org/10.1016/j.biomaterials.2013.07.061
Shine KM, Simson JA, Spector M (2009) Lubricin distribution in the human intervertebral disc. J Bone Joint Surg Am 91(9):2205–2212. https://doi.org/10.2106/jbjs.h.01344
Shine KM, Spector M (2008) The presence and distribution of lubricin in the caprine intervertebral disc. J Orthop Res 26(10):1398–1406. https://doi.org/10.1002/jor.20614
Shoulders MD, Raines RT (2009) Collagen structure and stability. Annu Rev Biochem 78:929–958. https://doi.org/10.1146/annurev.biochem.77.032207.120833
Silberberg R, Meier-Ruge W, Odermatt B (1989) Age-related changes in fibronectin in annulus fibrosus of the sand rat (Psammomys obesus). Exp Cell Biol 57(5):233–237. https://doi.org/10.1159/000163532
Singh K, Masuda K, Thonar EJ, An HS, Cs-Szabo G (2009) Age-related changes in the extracellular matrix of nucleus pulposus and anulus fibrosus of human intervertebral disc. Spine (Phila Pa 1976) 34(1):10–16. https://doi.org/10.1097/BRS.0b013e31818e5ddd
Sivan SS, Tsitron E, Wachtel E, Roughley PJ, Sakkee N, van der Ham F, DeGroot J, Roberts S, Maroudas A (2006) Aggrecan turnover in human intervertebral disc as determined by the racemization of aspartic acid. J Biol Chem 281(19):13009–13014. https://doi.org/10.1074/jbc.M600296200
Sivan SS, Van El B, Merkher Y, Schmelzer CE, Zuurmond AM, Heinz A, Wachtel E, Varga PP, Lazary A, Brayda-Bruno M et al (2012) Longevity of elastin in human intervertebral disc as probed by the racemization of aspartic acid. Biochim Biophys Acta 10:1671–1677. https://doi.org/10.1016/j.bbagen.2012.06.010
Sivan SS, Wachtel E, Roughley P (2014) Structure, function, aging and turnover of aggrecan in the intervertebral disc. Biochim Biophys Acta 1840(10):3181–3189. https://doi.org/10.1016/j.bbagen.2014.07.013
Sivan SS, Wachtel E, Tsitron E, Sakkee N, van der Ham F, Degroot J, Roberts S, Maroudas A (2008) Collagen turnover in normal and degenerate human intervertebral discs as determined by the racemization of aspartic acid. J Biol Chem 283(14):8796–8801. https://doi.org/10.1074/jbc.M709885200
Sloan SR Jr, Wipplinger C, Kirnaz S, Navarro-Ramirez R, Schmidt F, McCloskey D, Pannellini T, Schiavinato A, Härtl R, Bonassar LJ (2020) Combined nucleus pulposus augmentation and annulus fibrosus repair prevents acute intervertebral disc degeneration after discectomy. Sci Transl Med 12(534). https://doi.org/10.1126/scitranslmed.aay2380
Smith LJ, Byers S, Costi JJ, Fazzalari NL (2008) Elastic fibers enhance the mechanical integrity of the human lumbar anulus fibrosus in the radial direction. Ann Biomed Eng 36(2):214–223. https://doi.org/10.1007/s10439-007-9421-8
Smith SM, Melrose J (2019) Type XI collagen-perlecan-HS interactions stabilise the pericellular matrix of annulus fibrosus cells and chondrocytes providing matrix stabilisation and homeostasis. J Mol Histol 50(3):285–294. https://doi.org/10.1007/s10735-019-09823-1
Smith SM, Whitelock JM, Iozzo RV, Little CB, Melrose J (2009) Topographical variation in the distributions of versican, aggrecan and perlecan in the foetal human spine reflects their diverse functional roles in spinal development. Histochem Cell Biol 132(5):491–503. https://doi.org/10.1007/s00418-009-0623-z
Song H, Du H, Li J, Wang M, Wang J, Ju X, Mu W (2021) Effect of fibroblast growth factor 2 on degenerative endplate chondrocyte: from anabolism to catabolism. Exp Mol Pathol 118:104590. https://doi.org/10.1016/j.yexmp.2020.104590
Song Y, Wang Z, Liu L, Zhang S, Zhang H, Qian Y (2020) 1,4-Dihydropyridine (DHP) suppresses against oxidative stress in nucleus pulposus via activating sirtuin-1. Biomed Pharmacother 121:109592. https://doi.org/10.1016/j.biopha.2019.109592
Song YQ, Cheung KM, Ho DW, Poon SC, Chiba K, Kawaguchi Y, Hirose Y, Alini M, Grad S, Yee AF et al (2008) Association of the asporin D14 allele with lumbar-disc degeneration in Asians. Am J Hum Genet 82(3):744–747. https://doi.org/10.1016/j.ajhg.2007.12.017
Sowa G, Vadalà G, Studer R, Kompel J, Iucu C, Georgescu H, Gilbertson L, Kang J (2008) Characterization of intervertebral disc aging: longitudinal analysis of a rabbit model by magnetic resonance imaging, histology, and gene expression. Spine (Phila Pa 1976) 33(17):1821–1828. https://doi.org/10.1097/BRS.0b013e31817e2ce3
Specchia N, Pagnotta A, Toesca A, Greco F (2002) Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J 11(2):145–151. https://doi.org/10.1007/s00586-001-0361-y
Speer JE, Barcellona MN, Lu MY, Zha Z, Jing L, Gupta MC, Buchowski JM, Kelly MP, Setton LA (2021) Development of a library of laminin-mimetic peptide hydrogels for control of nucleus pulposus cell behaviors. J Tissue Eng 12:20417314211021220. https://doi.org/10.1177/20417314211021220
Suyama K, Sakai D, Hirayama N, Nakamura Y, Matsushita E, Terayama H, Qu N, Tanaka O, Sakabe K, Watanabe M (2018) Effects of interleukin-17A in nucleus pulposus cells and its small-molecule inhibitors for intervertebral disc disease. J Cell Mol Med 22(11):5539–5551. https://doi.org/10.1111/jcmm.13828
Sztrolovics R, Alini M, Mort JS, Roughley PJ (1999) Age-related changes in fibromodulin and lumican in human intervertebral discs. Spine (Phila Pa 1976) 24(17):1765–1771. https://doi.org/10.1097/00007632-199909010-00003
Sztrolovics R, Grover J, Cs-Szabo G, Shi SL, Zhang Y, Mort JS, Roughley PJ (2002) The characterization of versican and its message in human articular cartilage and intervertebral disc. J Orthop Res 20(2):257–266. https://doi.org/10.1016/s0736-0266(01)00110-3
Takegami K, Thonar EJ, An HS, Kamada H, Masuda K (2002) Osteogenic protein-1 enhances matrix replenishment by intervertebral disc cells previously exposed to interleukin-1. Spine (Phila Pa 1976) 27(12):1318–1325. https://doi.org/10.1097/00007632-200206150-00014
Tan X, Jain E, Barcellona MN, Morris E, Neal S, Gupta MC, Buchowski JM, Kelly M, Setton LA, Huebsch N (2021) Integrin and syndecan binding peptide-conjugated alginate hydrogel for modulation of nucleus pulposus cell phenotype. Biomaterials 277:121113. https://doi.org/10.1016/j.biomaterials.2021.121113
Teeple E, Aslani K, Shalvoy MR, Medrano JE, Zhang L, Machan JT, Fleming BC, Jay GD (2015) Lubricin deficiency in the murine lumbar intervertebral disc results in elevated torsional apparent modulus. J Biomech 48(10):2210–2213. https://doi.org/10.1016/j.jbiomech.2015.03.029
Tran CM, Schoepflin ZR, Markova DZ, Kepler CK, Anderson DG, Shapiro IM, Risbud MV (2014) CCN2 suppresses catabolic effects of interleukin-1β through α5β1 and αVβ3 integrins in nucleus pulposus cells: implications in intervertebral disc degeneration. J Biol Chem 289(11):7374–7387. https://doi.org/10.1074/jbc.M113.526111
Vo N, Couch B, Lee J, Sowa G, Kang J, Rebecca S (2020) Actions of prostaglandins on human nucleus pulposus metabolism inferred by cyclooxygenase 2 inhibition of cytokine activated cells. Neurospine 17(1):60–68. https://doi.org/10.14245/ns.2040050.025
Vo NV, Hartman RA, Yurube T, Jacobs LJ, Sowa GA, Kang JD (2013) Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J 13(3):331–341. https://doi.org/10.1016/j.spinee.2012.02.027
Vo NV, Sowa GA, Kang JD, Seidel C, Studer RK (2010) Prostaglandin E2 and prostaglandin F2α differentially modulate matrix metabolism of human nucleus pulposus cells. J Orthop Res 28(10):1259–1266. https://doi.org/10.1002/jor.21157
Wang D, Chen Y, Cao S, Ren P, Shi H, Li H, Xie L, Huang W, Shi B, Han J (2021a) Cyclic mechanical stretch ameliorates the degeneration of nucleus pulposus cells through promoting the ITGA2/PI3K/AKT signaling pathway. Oxid Med Cell Longev 2021:6699326. https://doi.org/10.1155/2021/6699326
Wang SZ, Chang Q, Lu J, Wang C (2015) Growth factors and platelet-rich plasma: promising biological strategies for early intervertebral disc degeneration. Int Orthop 39(5):927–934. https://doi.org/10.1007/s00264-014-2664-8
Wang Y, Bai B, Hu Y, Wang H, Liu N, Li Y, Li P, Zhou G, Zhou Q (2021b) Hydrostatic pressure modulates intervertebral disc cell survival and extracellular matrix homeostasis via regulating hippo-YAP/TAZ pathway. Stem Cells Int 2021:5626487. https://doi.org/10.1155/2021/5626487
Wang Z, Hutton WC, Yoon ST (2014) Bone morphogenetic protein-7 antagonizes tumor necrosis factor-α-induced activation of nuclear factor κB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II. Spine J 14(3):505–512. https://doi.org/10.1016/j.spinee.2013.08.016
Wang Z, Kim JH, Higashino K, Kim SS, Wang S, Seki S, Hutton WC, Yoon ST (2012) Cartilage intermediate layer protein (CILP) regulation in intervertebral discs. The effect of age, degeneration, and bone morphogenetic protein-2. Spine (Phila Pa 1976) 37(4):E203–208. https://doi.org/10.1097/BRS.0b013e31822dcf47
Wang Z, Weitzmann MN, Sangadala S, Hutton WC, Yoon ST (2013) Link protein N-terminal peptide binds to bone morphogenetic protein (BMP) type II receptor and drives matrix protein expression in rabbit intervertebral disc cells. J Biol Chem 288(39):28243–28253. https://doi.org/10.1074/jbc.M113.451948
Watanabe H, Yamada Y, Kimata K (1998) Roles of aggrecan, a large chondroitin sulfate proteoglycan, in cartilage structure and function. J Biochem 124(4):687–693. https://doi.org/10.1093/oxfordjournals.jbchem.a022166
Wei Y, Zhi-Hong W, Gui-Xing Q, Bin Y, Jun C, Yi-Peng W (2013) Extracellular signal-regulated kinase inhibition modulates rat annulus fibrosus cell response to interleukin-1. Spine (Phila Pa 1976) 38(17):E1075–1081. https://doi.org/10.1097/BRS.0b013e31829a6930
Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol 87(8–9):601–615. https://doi.org/10.1016/j.ejcb.2008.01.012
Wong J, Sampson SL, Bell-Briones H, Ouyang A, Lazar AA, Lotz JC, Fields AJ (2019) Nutrient supply and nucleus pulposus cell function: effects of the transport properties of the cartilage endplate and potential implications for intradiscal biologic therapy. Osteoarthritis Cartilage 27(6):956–964. https://doi.org/10.1016/j.joca.2019.01.013
Wu B, Meng C, Wang H, Jia C, Zhao Y (2016a) Changes of proteoglycan and collagen II of the adjacent intervertebral disc in the cervical instability models. Biomed Pharmacother 84:754–758. https://doi.org/10.1016/j.biopha.2016.09.077
Wu X, Li S, Wang K, Hua W, Li S, Song Y, Zhang Y, Yang S, Yang C (2019a) TNF-α regulates ITGβ1 and SYND4 expression in nucleus pulposus cells: activation of FAK/PI3K signaling. Inflammation 42(5):1575–1584. https://doi.org/10.1007/s10753-019-01019-9
Wu X, Liu W, Duan Z, Gao Y, Li S, Wang K, Song Y, Shao Z, Yang S, Yang C (2016b) The involvement of protease nexin-1 (PN1) in the pathogenesis of intervertebral disc (IVD) degeneration. Sci Rep 6:30563. https://doi.org/10.1038/srep30563
Wu X, Wang K, Hua W, Li S, Liu X, Song Y, Zhang Y, Shao Z, Li S, Yang C (2019b) Fibronectin induced ITGβ1/FAK-dependent apoptotic pathways determines the fate of degenerative NP cells. J Orthop Res 37(2):439–448. https://doi.org/10.1002/jor.24169
Xia M, Zhu Y (2008) Expression of integrin subunits in the herniated intervertebral disc. Connect Tissue Res 49(6):464–469. https://doi.org/10.1080/03008200802325425
Xiong C, Huang Y, Kang H, Zhang T, Xu F, Cai X (2017) Macrophage inhibition factor-mediated CD74 signal modulate inflammation and matrix metabolism in the degenerated cartilage endplate chondrocytes by activating extracellular signal regulated kinase 1/2. Spine (Phila Pa 1976) 42(2):E61-e70. https://doi.org/10.1097/brs.0000000000001726
Xu J, Liu S, Wang S, Qiu P, Chen P, Lin X, Fang X (2019) Decellularised nucleus pulposus as a potential biologic scaffold for disc tissue engineering. Mater Sci Eng C Mater Biol Appl 99:1213–1225. https://doi.org/10.1016/j.msec.2019.02.045
Yan Z, Pan Y, Wang S, Cheng M, Kong H, Sun C, Hu K, Chen T, Dong Q, Chen J (2017) Static compression induces ECM remodeling and integrin α2β1 expression and signaling in a rat tail caudal intervertebral disc degeneration model. Spine (Phila Pa 1976) 42(8):E448-e458. https://doi.org/10.1097/brs.0000000000001856
Yang H, Gao F, Li X, Wang J, Liu H, Zheng Z (2015) TGF-β1 antagonizes TNF-α induced up-regulation of matrix metalloproteinase 3 in nucleus pulposus cells: role of the ERK1/2 pathway. Connect Tissue Res 56(6):461–468. https://doi.org/10.3109/03008207.2015.1054030
Yang SD, Ma L, Gu TX, Ding WY, Zhang F, Shen Y, Zhang YZ, Yang DL, Zhang D, Sun YP et al (2014) 17β-Estradiol protects against apoptosis induced by levofloxacin in rat nucleus pulposus cells by upregulating integrin α2β1. Apoptosis 19(5):789–800. https://doi.org/10.1007/s10495-014-0965-4
Yang Z, Gao XJ, Zhao X (2020) CDMP1 promotes type II collagen and aggrecan synthesis of nucleus pulposus cell via the mediation of ALK6. Eur Rev Med Pharmacol Sci 24(21):10975–10983. https://doi.org/10.26355/eurrev_202011_23581
Yao Z, Nie L, Zhao Y, Zhang Y, Liu Y, Li J, Cheng L (2016) Salubrinal suppresses IL-17-induced upregulation of MMP-13 and extracellular matrix degradation through the NF-kB pathway in human nucleus pulposus cells. Inflammation 39(6):1997–2007. https://doi.org/10.1007/s10753-016-0435-y
Yee A, Lam MP, Tam V, Chan WC, Chu IK, Cheah KS, Cheung KM, Chan D (2016) Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis. Osteoarthritis Cartilage 24(3):503–513. https://doi.org/10.1016/j.joca.2015.09.020
Yin X, Motorwala A, Vesvoranan O, Levene HB, Gu W, Huang CY (2020) Effects of glucose deprivation on ATP and proteoglycan production of intervertebral disc cells under hypoxia. Sci Rep 10(1):8899. https://doi.org/10.1038/s41598-020-65691-w
Yu J, Schollum ML, Wade KR, Broom ND, Urban JP (2015) ISSLS prize winner: a detailed examination of the elastic network leads to a new understanding of annulus fibrosus organization. Spine (Phila Pa 1976) 40(15):1149–1157. https://doi.org/10.1097/brs.0000000000000943
Yu J, Tirlapur U, Fairbank J, Handford P, Roberts S, Winlove CP, Cui Z, Urban J (2007) Microfibrils, elastin fibres and collagen fibres in the human intervertebral disc and bovine tail disc. J Anat 210(4):460–471. https://doi.org/10.1111/j.1469-7580.2007.00707.x
Yu J, Winlove PC, Roberts S, Urban JP (2002) Elastic fibre organization in the intervertebral discs of the bovine tail. J Anat 201(6):465–475. https://doi.org/10.1046/j.1469-7580.2002.00111.x
Yurube T, Takada T, Suzuki T, Kakutani K, Maeno K, Doita M, Kurosaka M, Nishida K (2012) Rat tail static compression model mimics extracellular matrix metabolic imbalances of matrix metalloproteinases, aggrecanases, and tissue inhibitors of metalloproteinases in intervertebral disc degeneration. Arthritis Res Ther 14(2):R51. https://doi.org/10.1186/ar3764
Zappone B, Ruths M, Greene GW, Jay GD, Israelachvili JN (2007) Adsorption, lubrication, and wear of lubricin on model surfaces: polymer brush-like behavior of a glycoprotein. Biophys J 92(5):1693–1708. https://doi.org/10.1529/biophysj.106.088799
Zhang JF, Wang GL, Zhou ZJ, Fang XQ, Chen S, Fan SW (2018) Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and interleukins in vertebral cartilage endplate. Orthop Surg 10(4):306–311. https://doi.org/10.1111/os.12409
Zhang K, Ding W, Sun W, Sun XJ, Xie YZ, Zhao CQ, Zhao J (2016) Beta1 integrin inhibits apoptosis induced by cyclic stretch in annulus fibrosus cells via ERK1/2 MAPK pathway. Apoptosis 21(1):13–24. https://doi.org/10.1007/s10495-015-1180-7
Zhang S, Wang P, Hu B, Liu W, Lv X, Chen S, Shao Z (2021) HSP90 inhibitor 17-AAG attenuates nucleus pulposus inflammation and catabolism induced by M1-polarized macrophages. Front Cell Dev Biol 9:796974. https://doi.org/10.3389/fcell.2021.796974
Zhang YG, Guo X, Sun Z, Jia G, Xu P, Wang S (2010) Gene expression profiles of disc tissues and peripheral blood mononuclear cells from patients with degenerative discs. J Bone Miner Metab 28(2):209–219. https://doi.org/10.1007/s00774-009-0120-4
Zheng L, Cao Y, Ni S, Qi H, Ling Z, Xu X, Zou X, Wu T, Deng R, Hu B et al (2018) Ciliary parathyroid hormone signaling activates transforming growth factor-β to maintain intervertebral disc homeostasis during aging. Bone Res 6:21. https://doi.org/10.1038/s41413-018-0022-y
Zhou X, Wang J, Huang X, Fang W, Tao Y, Zhao T, Liang C, Hua J, Chen Q, Li F (2018) Injectable decellularized nucleus pulposus-based cell delivery system for differentiation of adipose-derived stem cells and nucleus pulposus regeneration. Acta Biomater 81:115–128. https://doi.org/10.1016/j.actbio.2018.09.044
Zhu J, Clark RAF (2014) Fibronectin at select sites binds multiple growth factors and enhances their activity: expansion of the collaborative ECM-GF paradigm. J Invest Dermatol 134(4):895–901. https://doi.org/10.1038/jid.2013.484
Zwambag DP, Molladavoodi S, Guerreiro MJ, DeWitte-Orr SJ, Gregory DE (2020) Immuno-stimulatory capacity of decorin in the rat tail intervertebral disc and the mechanical consequence of resultant inflammation. Eur Spine J. https://doi.org/10.1007/s00586-020-06469-6
Acknowledgements
Figure 2 was created with BioRender (https://biorender.com/).
Funding
This study was funded by the Major Research Plan of National Natural Science Foundation of China (91649204), the National Natural Science Foundation of China (81974352), the Natural Science Foundation of Hubei Province (2020CFB778), and the National Key Research and Development Program of China (2016YFC1100100).
Author information
Authors and Affiliations
Contributions
Zengwu Shao and Xiao Lv contributed to the conception and design of this review. Shuo Zhang, Weijian Liu, and Songfeng Chen performed searches, analyses, and interpretations. Peng Wang and Binwu Hu created the tables and figures. Baichuan Wang substantially revised the manuscript. All authors approved the version to be submitted. Shuo Zhang, Weijian Liu, and Songfeng Chen contributed equally to this work.
Corresponding authors
Ethics declarations
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Not applicable.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhang, S., Liu, W., Chen, S. et al. Extracellular matrix in intervertebral disc: basic and translational implications. Cell Tissue Res 390, 1–22 (2022). https://doi.org/10.1007/s00441-022-03662-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-022-03662-5