{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T06:52:51Z","timestamp":1773039171889,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2016,9,27]],"date-time":"2016-09-27T00:00:00Z","timestamp":1474934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Organ cultures are practical tools to investigate regenerative strategies for the intervertebral disc. However, most existing organ culture systems induce severe tissue degradation with only limited representation of the in vivo processes. The objective of this study was to develop a space- and cost-efficient tissue culture model, which represents degenerative processes of the nucleus pulposus (NP). Intact bovine NPs were cultured in a previously developed system using Dyneema jackets. Degenerative changes in the NP tissue were induced either by the direct injection of chondroitinase ABC (1\u201320 U\/mL) or by the diffusion of interleukin-1 beta (IL-1\u03b2) and tumor necrosis factor alpha (TNF-\u03b1) (both 100 ng\/mL) from the culture media. Extracellular matrix composition (collagens, proteoglycans, water, and DNA) and the expression of inflammatory and catabolic genes were analyzed. The anti-inflammatory and anti-catabolic compound epigallocatechin 3-gallate (EGCG, 10 \u00b5M) was employed to assess the relevance of the degenerative NP model. Although a single injection of chondroitinase ABC reduced the proteoglycan content in the NPs, it did not activate cellular responses. On the other hand, IL-1\u03b2 and TNF-\u03b1 significantly increased the mRNA expression of inflammatory mediators IL-6, IL-8, inducible nitric oxide synthase (iNOS), prostaglandin-endoperoxide synthase 2 (PTGS2) and matrix metalloproteinases (MMP1, MMP3, and MMP13). The cytokine-induced gene expression in the NPs was ameliorated with EGCG. This study provides a proof of concept that inflammatory NP cultures, with appropriate containment, can be useful for the discovery and evaluation of molecular therapeutic strategies against early degenerative disc disease.<\/jats:p>","DOI":"10.3390\/ijms17101640","type":"journal-article","created":{"date-parts":[[2016,9,27]],"date-time":"2016-09-27T10:14:11Z","timestamp":1474971251000},"page":"1640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["An Inflammatory Nucleus Pulposus Tissue Culture Model to Test Molecular Regenerative Therapies: Validation with Epigallocatechin 3-Gallate"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2041-8557","authenticated-orcid":false,"given":"Olga","family":"Krupkova","sequence":"first","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Hlavna","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Amir Tahmasseb","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Zvick","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Kunz","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"},{"name":"Health Department, ZHAW\u2014Zurich University of Applied Sciences, Technikumstrasse 71, CH-8401 Winterthur, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7372-4072","authenticated-orcid":false,"given":"Keita","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Eindhoven University of Technology, Postbus 513, 5600 MB Eindhoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"},{"name":"Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-4629","authenticated-orcid":false,"given":"Karin","family":"Wuertz-Kozak","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland"},{"name":"Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1097\/01.brs.0000146499.97948.52","article-title":"Nutrition of the intervertebral disc","volume":"29","author":"Urban","year":"2004","journal-title":"Spine"},{"key":"ref_2","first-page":"1033","article-title":"Intervertebral disc biology, degeneration and novel tissue engineering and regenerative medicine therapies","volume":"22","author":"Richardson","year":"2007","journal-title":"Histol. Histopathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104","DOI":"10.22203\/eCM.v030a08","article-title":"Disc in flames: Roles of TNF-\u03b1 and IL-1\u03b2 in intervertebral disc degeneration","volume":"30","author":"Johnson","year":"2015","journal-title":"Eur. Cells Mater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R45","DOI":"10.1186\/ar2198","article-title":"Accelerated cellular senescence in degenerate intervertebral discs: A possible role in the pathogenesis of intervertebral disc degeneration","volume":"9","author":"Freemont","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R732","DOI":"10.1186\/ar1732","article-title":"The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration","volume":"7","author":"Freemont","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1186\/ar2275","article-title":"Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1\u03b2 and TNF-\u03b1 expression profile","volume":"9","author":"Hoyland","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.bbrc.2013.02.034","article-title":"A role for TNF-\u03b1 in intervertebral disc degeneration: A non-recoverable catabolic shift","volume":"433","author":"Purmessur","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00776-003-0759-y","article-title":"Degeneration of intervertebral discs due to smoking: Experimental assessment in a rat-smoking model","volume":"9","author":"Oda","year":"2004","journal-title":"J. Orthop. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1002\/jor.22946","article-title":"Reduced tonicity stimulates an inflammatory response in nucleus pulposus tissue that can be limited by a COX-2-specific inhibitor","volume":"33","author":"Potier","year":"2015","journal-title":"J. Orthop. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.spinee.2012.02.027","article-title":"Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration","volume":"13","author":"Vo","year":"2013","journal-title":"Spine J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"372","DOI":"10.22203\/eCM.v028a26","article-title":"Epigallocatechin 3-gallate suppresses interleukin-1\u03b2-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats","volume":"28","author":"Krupkova","year":"2014","journal-title":"Eur. Cells Mater."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1055\/s-0033-1347299","article-title":"Inflammatory mediators in intervertebral disk degeneration and discogenic pain","volume":"3","author":"Wuertz","year":"2013","journal-title":"Glob. Spine J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: Pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_14","first-page":"75","article-title":"Matrix degradation by chondrocytes in the intervertebral disc is mediated by interleukin-1","volume":"40","author":"Freemont","year":"2001","journal-title":"Rheumatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.cca.2015.06.023","article-title":"MMPs and ADAMTSs in intervertebral disc degeneration","volume":"448","author":"Wang","year":"2015","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1097\/01.brs.0000231761.73859.2c","article-title":"What is intervertebral disc degeneration, and what causes it?","volume":"31","author":"Adams","year":"2006","journal-title":"Spine"},{"key":"ref_17","first-page":"S324","article-title":"Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility","volume":"23","author":"Galbusera","year":"2014","journal-title":"Eur. Spine J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0030-5898(20)31644-8","article-title":"The tissue origin of low back pain and sciatica: A report of pain response to tissue stimulation during operations on the lumbar spine using local anesthesia","volume":"22","author":"Kuslich","year":"1991","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0140-6736(97)02135-1","article-title":"Nerve ingrowth into diseased intervertebral disc in chronic back pain","volume":"350","author":"Freemont","year":"1997","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1097\/BRS.0b013e3182608ac4","article-title":"Issls prize winner: Lumbar vertebral endplate lesions associations with disc degeneration and back pain history","volume":"37","author":"Wang","year":"2012","journal-title":"Spine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0030-5898(03)00101-9","article-title":"Low back pain: An economic assessment in the United States","volume":"35","author":"Pai","year":"2004","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.berh.2013.09.009","article-title":"Evidence for surgery in degenerative lumbar spine disorders","volume":"27","author":"Jacobs","year":"2013","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1097\/BRS.0000000000000052","article-title":"Rate of adjacent segment disease in cervical disc arthroplasty versus single-level fusion: Meta-analysis of prospective studies","volume":"38","author":"Verma","year":"2013","journal-title":"Spine"},{"key":"ref_24","first-page":"w13598","article-title":"Intervertebral disc regeneration or repair with biomaterials and stem cell therapy\u2014Feasible or fiction?","volume":"142","author":"Chan","year":"2012","journal-title":"Swiss Med. Wkly."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.addr.2014.06.009","article-title":"Advancing the cellular and molecular therapy for intervertebral disc disease","volume":"84","author":"Sakai","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrrheum.2015.13","article-title":"Stem cell therapy for intervertebral disc regeneration: Obstacles and solutions","volume":"11","author":"Sakai","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Illien-Junger, S., Grosjean, F., Laudier, D.M., Vlassara, H., Striker, G.E., and Iatridis, J.C. (2013). Combined anti-inflammatory and anti-age drug treatments have a protective effect on intervertebral discs in mice with diabetes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064302"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/ar4353","article-title":"Enhancing intervertebral disc repair and regeneration through biology: Platelet-rich plasma as an alternative strategy","volume":"15","author":"Wang","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.1089\/ten.tea.2008.0697","article-title":"Characterization of in vivo effects of platelet-rich plasma and biodegradable gelatin hydrogel microspheres on degenerated intervertebral discs","volume":"15","author":"Sawamura","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107","DOI":"10.22203\/eCM.v026a08","article-title":"Best paper NASS 2013: Link-N can stimulate proteoglycan synthesis in the degenerated human intervertebral discs","volume":"26","author":"Gawri","year":"2013","journal-title":"Eur. Cells Mater."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1055\/s-0033-1349400","article-title":"Molecular therapy for disk degeneration and pain","volume":"3","author":"Mwale","year":"2013","journal-title":"Glob. Spine J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0021-9290(03)00250-1","article-title":"Fluid flow and convective transport of solutes within the intervertebral disc","volume":"37","author":"Ferguson","year":"2004","journal-title":"J. Biomech."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/01635581.2011.523502","article-title":"Targeting cell signaling and apoptotic pathways by dietary agents: Role in the prevention and treatment of cancer","volume":"63","author":"Shanmugam","year":"2011","journal-title":"Nutr. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E1373","DOI":"10.1097\/BRS.0b013e318221e655","article-title":"The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo","volume":"36","author":"Wuertz","year":"2011","journal-title":"Spine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1476-9255-9-29","article-title":"Curcuma DMSO extracts and curcumin exhibit an anti-inflammatory and anti-catabolic effect on human intervertebral disc cells, possibly by influencing TLR2 expression and JNK activity","volume":"9","author":"Klawitter","year":"2012","journal-title":"J. Inflamm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S850","DOI":"10.1007\/s00586-011-1919-y","article-title":"Triptolide exhibits anti-inflammatory, anti-catabolic as well as anabolic effects and suppresses TLR expression and MAPK activity in IL-1\u03b2 treated human intervertebral disc cells","volume":"21","author":"Klawitter","year":"2012","journal-title":"Eur. Spine J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7031397","DOI":"10.1155\/2016\/7031397","article-title":"The natural polyphenol epigallocatechin gallate protects intervertebral disc cells from oxidative stress","volume":"2016","author":"Krupkova","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"292S","DOI":"10.1093\/ajcn\/81.1.292S","article-title":"Polyphenols and cardiovascular disease: Effects on endothelial and platelet function","volume":"81","author":"Vita","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2174\/1574888X10666150312102948","article-title":"Organ culture bioreactors\u2014Platforms to study human intervertebral disc degeneration and regenerative therapy","volume":"10","author":"Gantenbein","year":"2015","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1097\/BRS.0b013e3181f81314","article-title":"Development of an organ culture system for long-term survival of the intact human intervertebral disc","volume":"36","author":"Gawri","year":"2011","journal-title":"Spine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1007\/s00586-011-1721-x","article-title":"Development of an intact intervertebral disc organ culture system in which degeneration can be induced as a prelude to studying repair potential","volume":"20","author":"Jim","year":"2011","journal-title":"Eur. Spine J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.spinee.2012.12.007","article-title":"Papain-induced in vitro disc degeneration model for the study of injectable nucleus pulposus therapy","volume":"13","author":"Chan","year":"2013","journal-title":"Spine J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bucher, C., Gazdhar, A., Benneker, L.M., Geiser, T., and Gantenbein-Ritter, B. (2013). Nonviral gene delivery of growth and differentiation factor 5 to human mesenchymal stem cells injected into a 3D bovine intervertebral disc organ culture system. Stem Cells Int., 2013.","DOI":"10.1155\/2013\/326828"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/jor.21573","article-title":"Fracture of the vertebral endplates, but not equienergetic impact load, promotes disc degeneration in vitro","volume":"30","author":"Dudli","year":"2012","journal-title":"J. Orthop. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/01.brs.0000251013.07656.45","article-title":"Stab incision for inducing intervertebral disc degeneration in the rat","volume":"32","author":"Rousseau","year":"2007","journal-title":"Spine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1002\/jor.23325","article-title":"Longitudinal changes in the structure and inflammatory response of the intervertebral disc due to stab injury in a murine organ culture model","volume":"34","author":"Abraham","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1186\/ar4301","article-title":"An organ culture system to model early degenerative changes of the intervertebral disc II: Profiling global gene expression changes","volume":"15","author":"Markova","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1089\/ten.tec.2015.0195","article-title":"A degenerative\/proinflammatory intervertebral disc organ culture: An ex vivo model for anti-inflammatory drug and cell therapy","volume":"22","author":"Teixeira","year":"2016","journal-title":"Tissue Eng."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.spinee.2012.12.006","article-title":"Long-term culture of bovine nucleus pulposus explants in a native environment","volume":"13","author":"Potier","year":"2013","journal-title":"Spine J."},{"key":"ref_50","first-page":"103","article-title":"Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-\u03baB and map kinases","volume":"23","author":"Wuertz","year":"2012","journal-title":"Eur. Cells Mater."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s00586-007-0414-y","article-title":"Are animal models useful for studying human disc disorders\/degeneration?","volume":"17","author":"Alini","year":"2008","journal-title":"Eur. Spine J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1089\/ten.tea.2015.0121","article-title":"The stimulatory effect of notochordal cell-conditioned medium in a nucleus pulposus explant culture","volume":"22","author":"Meij","year":"2016","journal-title":"Tissue Eng."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Van Dijk, B.G., Potier, E., van Dijk, M., Creemers, L.B., and Ito, K. (2015). Osteogenic protein 1 does not stimulate a regenerative effect in cultured human degenerated nucleus pulposus tissue. J. Tissue Eng. Regen. Med.","DOI":"10.1002\/term.2111"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E1377","DOI":"10.1097\/BRS.0b013e31829ffde8","article-title":"Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model","volume":"38","author":"Furtwangler","year":"2013","journal-title":"Spine"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"21335","DOI":"10.1074\/jbc.M112.341032","article-title":"Detrimental role for human high temperature requirement serine protease A1 (HTRA1) in the pathogenesis of intervertebral disc (IVD) degeneration","volume":"287","author":"Tiaden","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/BF00179970","article-title":"The effect of chondroitinase ABC on rabbit intervertebral disc\u2014Radiological, histological and electron-microscopic finding","volume":"19","author":"Park","year":"1995","journal-title":"Int. Orthop."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1055\/s-0033-1347300","article-title":"Mechanisms of intervertebral disk degeneration\/injury and pain: A review","volume":"3","author":"Ito","year":"2013","journal-title":"Glob. Spine J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1097\/00007632-199602010-00003","article-title":"Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2","volume":"21","author":"Kang","year":"1996","journal-title":"Spine"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1097\/00007632-199705150-00003","article-title":"Toward a biochemical understanding of human intervertebral disc degeneration and herniation: Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases","volume":"22","author":"Kang","year":"1997","journal-title":"Spine"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"R126","DOI":"10.1186\/ar2793","article-title":"Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc","volume":"11","author":"Richardson","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1186\/ar2487","article-title":"Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc","volume":"10","author":"Purmessur","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_62","first-page":"10","article-title":"Histology and pathology of the human intervertebral disc","volume":"88","author":"Roberts","year":"2006","journal-title":"J. Bone Jt. Surg."},{"key":"ref_63","first-page":"294","article-title":"Basic and clinical anatomy of the spine, spinal cord, and ANS","volume":"20","author":"Cramer","year":"1997","journal-title":"J. Manip. Physiol. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jbspin.2005.03.003","article-title":"Pathophysiology of disk-related sciatica. I.\u2014Evidence supporting a chemical component","volume":"73","author":"Mulleman","year":"2006","journal-title":"Jt. Bone Spine"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"R171","DOI":"10.1186\/ar3494","article-title":"An organ culture system to model early degenerative changes of the intervertebral disc","volume":"13","author":"Ponnappan","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1097\/PHM.0b013e31825f145a","article-title":"Cells from degenerative intervertebral discs demonstrate unfavorable responses to mechanical and inflammatory stimuli: A pilot study","volume":"91","author":"Sowa","year":"2012","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1097\/BRS.0b013e31811ebac5","article-title":"Experimental intervertebral disc degeneration induced by chondroitinase ABC in the goat","volume":"32","author":"Hoogendoorn","year":"2007","journal-title":"Spine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.spinee.2006.09.005","article-title":"Matrix replenishment by intervertebral disc cells after chemonucleolysis in vitro with chondroitinase ABC and chymopapain","volume":"7","author":"Chiba","year":"2007","journal-title":"Spine J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.14440\/jbm.2015.40","article-title":"Extraction of rna from tough tissues with high proteoglycan content by cryosection, second phase separation and high salt precipitation","volume":"2","author":"Juliana","year":"2015","journal-title":"J. Biol. Methods"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3109\/03008208209160269","article-title":"A direct spectrophotometric microassay for sulfated glycosaminoglycans in cartilage cultures","volume":"9","author":"Farndale","year":"1982","journal-title":"Connect. Tissue Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1007\/s00586-014-3301-3","article-title":"Persistent degenerative changes in the intervertebral disc after burst fracture in an in vitro model mimicking physiological post-traumatic conditions","volume":"24","author":"Dudli","year":"2015","journal-title":"Eur. Spine J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/10\/1640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:31:52Z","timestamp":1760211112000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/10\/1640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,27]]},"references-count":71,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2016,10]]}},"alternative-id":["ijms17101640"],"URL":"https:\/\/doi.org\/10.3390\/ijms17101640","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,27]]}}}