{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:58:29Z","timestamp":1793318309411,"version":"4.5.0"},"reference-count":49,"publisher":"Elsevier BV","issue":"1","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270887"],"award-info":[{"award-number":["32270887"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272507"],"award-info":[{"award-number":["82272507"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32200654"],"award-info":[{"award-number":["32200654"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82430079"],"award-info":[{"award-number":["82430079"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472519"],"award-info":[{"award-number":["82472519"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Development Program of China","award":["2022YFA1103202"],"award-info":[{"award-number":["2022YFA1103202"]}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"crossref","award":["CSTB2023NSCQ\u2011ZDJO008"],"award-info":[{"award-number":["CSTB2023NSCQ\u2011ZDJO008"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Postdoctoral Innovative Talent Support Program","award":["BX20220397"],"award-info":[{"award-number":["BX20220397"]}]},{"DOI":"10.13039\/501100011277","name":"State Key Laboratory of Trauma, Burns and Combined Injury","doi-asserted-by":"publisher","award":["SFLKF202201"],"award-info":[{"award-number":["SFLKF202201"]}],"id":[{"id":"10.13039\/501100011277","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Project for Enhancing Innovation of Army Medical University","award":["2023XJS39"],"award-info":[{"award-number":["2023XJS39"]}]},{"name":"Talent Innovation Training Program at the Army Medical Center","award":["ZXZYTSYS09"],"award-info":[{"award-number":["ZXZYTSYS09"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Military Med Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lumbar disc degeneration (LDD) displays considerable heterogeneity in terms of clinical features and pathological changes. However, researchers have not clearly determined whether the transcriptome variations in LDD could be used to identify or interpret the causes of heterogeneity in clinical features. This study aimed to identify the transcriptomic classification of degenerated discs in LDD patients and whether the molecular subtypes of LDD could be accurately predicted using clinical features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>One hundred and twenty-two nucleus pulposus (NP) tissues from 108 patients were consecutively collected for bulk RNA sequencing (RNA-seq). An unsupervised clustering method was employed to analyze the bulk RNA matrix. Differential analysis was performed to characterize the transcriptional signatures and subtype-specific extracellular matrix (ECM) dysregulation. The cell subpopulation states of each subtype were inferred by integrating bulk and single-cell sequencing datasets. Transwell and dual-luciferase reporter gene assays were employed to investigate possible molecular mechanisms involved. Machine learning algorithm diagnostic prediction models were developed to correlate molecular classification with clinical features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LDD was classified into 4 subtypes with distinct molecular signatures and ECM remodeling: C1 with collagenesis, C2 with ossification, C3 with low chondrogenesis, and C4 with fibrogenesis. Chond1-3 in C1 dominated disc collagenesis via the activation of the mechanosensors\n                      <jats:italic>TRPV4<\/jats:italic>\n                      and\n                      <jats:italic>PIEZO1<\/jats:italic>\n                      ; NP progenitor cells in C2 exhibited chondrogenic and osteogenic phenotypes; Chond1 in C3 was linked to a disrupted hypoxic microenvironment leading to reduced chondrogenesis; Macrophages in C4 played a crucial role in disc fibrogenesis via the secretion of tumor necrosis factor-\u03b1 (TNF-\u03b1). Furthermore, the random forest diagnostic prediction model was proven to have a robust performance [area under the receiver operating characteristic (ROC) curve: 0.9312; accuracy: 0.84] in stratifying the molecular subtypes of LDD based on 12 clinical features.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study delineates 4 distinct molecular subtypes of LDD that can be accurately stratified on the basis of clinical features. The identification of these subtypes would facilitate precise diagnostics and guide the development of personalized treatment strategies for LDD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40779-025-00637-9","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T04:44:33Z","timestamp":1756442673000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical-transcriptomic classification of lumbar disc degeneration enhanced by machine learning"],"prefix":"10.1016","volume":"12","author":[{"given":"Huai-Jian","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yuan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ou","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Bo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Gang","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu-Lin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Li","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Bo","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"issue":"Suppl 2","key":"637_CR1","first-page":"3","volume":"88","author":"MC Batti\u00e9","year":"2006","unstructured":"Batti\u00e9 MC, Videman T. Lumbar disc degeneration: epidemiology and genetics. J Bone Joint Surg Am. 2006;88(Suppl 2):3\u20139.","journal-title":"J Bone Joint Surg Am"},{"key":"637_CR2","unstructured":"GBD 2021 Low Back Pain Collaborators. Global, regional, and national burden of low back pain, 1990-2020, its attributable risk factors, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(6):e316\u201329."},{"issue":"18","key":"637_CR3","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1056\/NEJMcp1512658","volume":"374","author":"RA Deyo","year":"2016","unstructured":"Deyo RA, Mirza SK. Clinical practice herniated lumbar intervertebral disk. N Engl J Med. 2016;374(18):1763\u201372.","journal-title":"N Engl J Med"},{"issue":"3","key":"637_CR4","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1097\/00007632-198704000-00016","volume":"12","author":"G Schneiderman","year":"1987","unstructured":"Schneiderman G, Flannigan B, Kingston S, Thomas J, Dillin WH, Watkins RG. Magnetic resonance imaging in the diagnosis of disc degeneration: correlation with discography. Spine. 1987;12(3):276\u201381.","journal-title":"Spine"},{"issue":"5","key":"637_CR5","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1097\/00007632-199005000-00012","volume":"15","author":"JP Thompson","year":"1990","unstructured":"Thompson JP, Pearce RH, Schechter MT, Adams ME, Tsang IK, Bishop PB. Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc. Spine. 1990;15(5):411\u20135.","journal-title":"Spine"},{"issue":"23","key":"637_CR6","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1097\/00007632-200212010-00002","volume":"27","author":"N Boos","year":"2002","unstructured":"Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine. 2002;27(23):2631\u201344.","journal-title":"Spine"},{"issue":"17","key":"637_CR7","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1097\/00007632-200109010-00011","volume":"26","author":"CW Pfirrmann","year":"2001","unstructured":"Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine. 2001;26(17):1873\u20138.","journal-title":"Spine"},{"issue":"1","key":"637_CR8","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41536-022-00245-4","volume":"7","author":"B Peng","year":"2022","unstructured":"Peng B, Li Y. Concerns about cell therapy for intervertebral disc degeneration. NPJ Regen Med. 2022;7(1):46.","journal-title":"NPJ Regen Med"},{"issue":"4","key":"637_CR9","doi-asserted-by":"publisher","first-page":"e1036","DOI":"10.1002\/jsp2.1036","volume":"1","author":"LJ Smith","year":"2018","unstructured":"Smith LJ, Silverman L, Sakai D, Le Maitre CL, Mauck RL, Malhotra NR, et al. Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: recommendations of the ORS spine section. JOR Spine. 2018;1(4):e1036.","journal-title":"JOR Spine"},{"issue":"5","key":"637_CR10","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1017\/thg.2016.68","volume":"19","author":"MB Pinheiro","year":"2016","unstructured":"Pinheiro MB, Ferreira ML, Refshauge K, Hopper J, Maher CG, Hartvigsen J, et al. Protective and harmful effects of physical activity for low back pain: a protocol for the Australian twin back pain (AUTBACK) feasibility study. Twin Res Hum Genet. 2016;19(5):502\u20139.","journal-title":"Twin Res Hum Genet"},{"issue":"3","key":"637_CR11","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3390\/medicina57030248","volume":"57","author":"M Piroska","year":"2021","unstructured":"Piroska M, Tarnoki DL, Szabo H, Jokkel Z, Meszaros S, Horvath C, et al. Strong genetic effects on bone mineral density in multiple locations with two different techniques: results from a cross-sectional twin study. Medicina (Kaunas). 2021;57(3):248.","journal-title":"Medicina (Kaunas)."},{"issue":"1","key":"637_CR12","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41413-020-00109-x","volume":"8","author":"C Yuan","year":"2020","unstructured":"Yuan C, Pan Z, Zhao K, Li J, Sheng Z, Yao X, et al. Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas. Bone Res. 2020;8(1):38.","journal-title":"Bone Res"},{"issue":"7987","key":"637_CR13","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41586-023-06708-y","volume":"623","author":"F Zhang","year":"2023","unstructured":"Zhang F, Jonsson AH, Nathan A, Millard N, Curtis M, Xiao Q, et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature. 2023;623(7987):616\u201324.","journal-title":"Nature"},{"issue":"5","key":"637_CR14","doi-asserted-by":"publisher","first-page":"e13148","DOI":"10.1111\/acel.13148","volume":"19","author":"EJ Novais","year":"2020","unstructured":"Novais EJ, Tran VA, Miao J, Slaver K, Sinensky A, Dyment NA, et al. Comparison of inbred mouse strains shows diverse phenotypic outcomes of intervertebral disc aging. Aging Cell. 2020;19(5):e13148.","journal-title":"Aging Cell"},{"issue":"11","key":"637_CR15","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.1016\/j.spinee.2014.04.022","volume":"14","author":"DF Fardon","year":"2014","unstructured":"Fardon DF, Williams AL, Dohring EJ, Murtagh FR, Rothman SLG, Sze GK. Lumbar disc nomenclature: version 2.0: recommendations of the combined task forces of the North American sSpine Society, the American Society of Spine radiology and the American Society of Neuroradiology. Spine J. 2014;14(11):2525\u201345.","journal-title":"Spine J"},{"issue":"5","key":"637_CR16","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s41576-018-0088-9","volume":"20","author":"VY Kiselev","year":"2019","unstructured":"Kiselev VY, Andrews TS, Hemberg M. Challenges in unsupervised clustering of single-cell RNA-seq data. Nat Rev Genet. 2019;20(5):273\u201382.","journal-title":"Nat Rev Genet"},{"issue":"5","key":"637_CR17","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1038\/nmeth.4236","volume":"14","author":"VY Kiselev","year":"2017","unstructured":"Kiselev VY, Kirschner K, Schaub MT, Andrews T, Yiu A, Chandra T, et al. SC3: consensus clustering of single-cell RNA-seq data. Nat Methods. 2017;14(5):483\u20136.","journal-title":"Nat Methods"},{"issue":"7","key":"637_CR18","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.","journal-title":"Nucleic Acids Res"},{"issue":"22","key":"637_CR19","doi-asserted-by":"publisher","first-page":"e169554","DOI":"10.1172\/jci.insight.169554","volume":"8","author":"TS Nelson","year":"2023","unstructured":"Nelson TS, Allen HN, Basu P, Prasoon P, Nguyen E, Arokiaraj CM, et al. Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp. JCI Insight. 2023;8(22):e169554.","journal-title":"JCI Insight"},{"issue":"3","key":"637_CR20","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/S0896-6273(02)01002-4","volume":"36","author":"F Ledda","year":"2002","unstructured":"Ledda F, Paratcha G, Ib\u00e1\u00f1ez CF. Target-derived GFRalpha1 as an attractive guidance signal for developing sensory and sympathetic axons via activation of Cdk5. Neuron. 2002;36(3):387\u2013401.","journal-title":"Neuron"},{"issue":"3","key":"637_CR21","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.cellsig.2007.10.023","volume":"20","author":"A Ben-Zvi","year":"2008","unstructured":"Ben-Zvi A, Ben-Gigi L, Yagil Z, Lerman O, Behar O. Semaphorin3A regulates axon growth independently of growth cone repulsion via modulation of TrkA signaling. Cell Signal. 2008;20(3):467\u201379.","journal-title":"Cell Signal"},{"issue":"2","key":"637_CR22","doi-asserted-by":"publisher","first-page":"e1247","DOI":"10.1002\/jsp2.1247","volume":"6","author":"T Tang","year":"2023","unstructured":"Tang T, Zhu Z, He Z, Wang F, Chen H, Liu S, et al. DLX5 regulates the osteogenic differentiation of spinal ligaments cells derived from ossification of the posterior longitudinal ligament patients via NOTCH signaling. JOR Spine. 2023;6(2):e1247.","journal-title":"JOR Spine"},{"issue":"2","key":"637_CR23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41422-023-00918-9","volume":"34","author":"M Wu","year":"2024","unstructured":"Wu M, Wu S, Chen W, Li YP. The roles and regulatory mechanisms of TGF-\u03b2 and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res. 2024;34(2):101\u201323.","journal-title":"Cell Res"},{"issue":"11","key":"637_CR24","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1016\/j.cmet.2022.09.005","volume":"34","author":"E Fern\u00e1ndez-Vizarra","year":"2022","unstructured":"Fern\u00e1ndez-Vizarra E, L\u00f3pez-Calcerrada S, Sierra-Magro A, P\u00e9rez-P\u00e9rez R, Formosa LE, Hock DH, et al. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metab. 2022;34(11):1792-1808.e6.","journal-title":"Cell Metab"},{"issue":"D1","key":"637_CR25","doi-asserted-by":"publisher","first-page":"D1519","DOI":"10.1093\/nar\/gkac1009","volume":"51","author":"X Shao","year":"2023","unstructured":"Shao X, Gomez CD, Kapoor N, Considine JM, Grams C, Gao YT, et al. MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge database. Nucleic Acids Res. 2023;51(D1):D1519-30.","journal-title":"Nucleic Acids Res"},{"key":"637_CR26","doi-asserted-by":"publisher","first-page":"1136777","DOI":"10.3389\/fcell.2023.1136777","volume":"11","author":"X Yang","year":"2023","unstructured":"Yang X, Lu Y, Zhou H, Jiang HT, Chu L. Integrated proteome sequencing, bulk RNA sequencing and single-cell RNA sequencing to identify potential biomarkers in different grades of intervertebral disc degeneration. Front Cell Dev Biol. 2023;11:1136777.","journal-title":"Front Cell Dev Biol."},{"issue":"7","key":"637_CR27","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1136\/ard.53.7.455","volume":"53","author":"PJ Verschure","year":"1994","unstructured":"Verschure PJ, Joosten LA, van der Kraan PM, Van den Berg WB. Responsiveness of articular cartilage from normal and inflamed mouse knee joints to various growth factors. Ann Rheum Dis. 1994;53(7):455\u201360.","journal-title":"Ann Rheum Dis"},{"issue":"10","key":"637_CR28","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1002\/cbin.11851","volume":"46","author":"B Ding","year":"2022","unstructured":"Ding B, Xiao L, Xu H. YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension. Cell Biol Int. 2022;46(10):1637\u201348.","journal-title":"Cell Biol Int."},{"issue":"2","key":"637_CR29","doi-asserted-by":"publisher","first-page":"e22714","DOI":"10.1096\/fj.202201388R","volume":"37","author":"GWD Easson","year":"2023","unstructured":"Easson GWD, Savadipour A, Anandarajah A, Iannucci LE, Lake SP, Guilak F, et al. Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc. FASEB J. 2023;37(2):e22714.","journal-title":"FASEB J"},{"key":"637_CR30","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.matbio.2024.01.005","volume":"127","author":"R Zhao","year":"2024","unstructured":"Zhao R, Dong J, Liu C, Li M, Tan R, Fei C, et al. Thrombospondin-1 promotes mechanical stress-mediated ligamentum flavum hypertrophy through the TGF\u03b21\/Smad3 signaling pathway. Matrix Biol. 2024;127:8\u201322.","journal-title":"Matrix Biol"},{"issue":"6","key":"637_CR31","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.joca.2015.02.011","volume":"23","author":"L Xu","year":"2015","unstructured":"Xu L, Li Z, Liu SY, Xu SY, Ni GX. Asporin and osteoarthritis. Osteoarthritis Cartilage. 2015;23(6):933\u20139.","journal-title":"Osteoarthritis Cartilage"},{"issue":"4","key":"637_CR32","doi-asserted-by":"publisher","first-page":"101224","DOI":"10.1016\/j.jbc.2021.101224","volume":"297","author":"K Bubb","year":"2021","unstructured":"Bubb K, Holzer T, Nolte JL, Kr\u00fcger M, Wilson R, Schl\u00f6tzer-Schrehardt U, et al. Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage. J Biol Chem. 2021;297(4):101224.","journal-title":"J Biol Chem"},{"issue":"1","key":"637_CR33","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1007\/s10753-022-01732-y","volume":"46","author":"W Yang","year":"2023","unstructured":"Yang W, Jia C, Liu L, Fu Y, Wu Y, Liu Z, et al. Hypoxia-inducible factor-1\u03b1 protects against intervertebral disc degeneration through antagonizing mitochondrial oxidative stress. Inflammation. 2023;46(1):270\u201384.","journal-title":"Inflammation"},{"issue":"12","key":"637_CR34","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1136\/ard.2007.077800","volume":"67","author":"PLEM van Lent","year":"2008","unstructured":"van Lent PLEM, Grevers L, Blom AB, Sloetjes A, Mort JS, Vogl T, et al. Myeloid-related proteins S100A8\/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis. Ann Rheum Dis. 2008;67(12):1750\u20138.","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"637_CR35","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1002\/jcp.25720","volume":"232","author":"J Diaz-Romero","year":"2017","unstructured":"Diaz-Romero J, Nesic D. S100A1 and S100B: calcium sensors at the cross-roads of multiple chondrogenic pathways. J Cell Physiol. 2017;232(8):1979\u201387.","journal-title":"J Cell Physiol"},{"issue":"6","key":"637_CR36","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1016\/j.ajpath.2013.02.037","volume":"182","author":"Y Tian","year":"2013","unstructured":"Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-\u03baB. Am J Pathol. 2013;182(6):2310\u201321.","journal-title":"Am J Pathol"},{"key":"637_CR37","doi-asserted-by":"publisher","first-page":"922173","DOI":"10.3389\/fimmu.2022.922173","volume":"13","author":"XC Li","year":"2022","unstructured":"Li XC, Luo SJ, Fan W, Zhou TL, Tan DQ, Tan RX, et al. Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism. Front Immunol. 2022;13:922173.","journal-title":"Front Immunol"},{"issue":"1","key":"637_CR38","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41413-021-00163-z","volume":"9","author":"Y Gan","year":"2021","unstructured":"Gan Y, He J, Zhu J, Xu Z, Wang Z, Yan J, et al. Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs. Bone Res. 2021;9(1):37.","journal-title":"Bone Res."},{"issue":"3","key":"637_CR39","doi-asserted-by":"publisher","first-page":"e2103631","DOI":"10.1002\/advs.202103631","volume":"9","author":"J Tu","year":"2022","unstructured":"Tu J, Li W, Yang S, Yang P, Yan Q, Wang S, et al. Single-cell transcriptome profiling reveals multicellular ecosystem of nucleus pulposus during degeneration progression. Adv Sci (Weinh). 2022;9(3):e2103631.","journal-title":"Adv Sci (Weinh)"},{"issue":"4","key":"637_CR40","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s43018-022-00356-3","volume":"3","author":"T Chu","year":"2022","unstructured":"Chu T, WangPe\u2019erDanko ZDCG. Cell type and gene expression deconvolution with BayesPrism enables Bayesian integrative analysis across bulk and single-cell RNA sequencing in oncology. Nat Cancer. 2022;3(4):505\u201317.","journal-title":"Nat Cancer"},{"issue":"5","key":"637_CR41","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","volume":"12","author":"AM Newman","year":"2015","unstructured":"Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453\u20137.","journal-title":"Nat Methods"},{"issue":"4","key":"637_CR42","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41587-021-01091-3","volume":"40","author":"D Sun","year":"2022","unstructured":"Sun D, Guan X, Moran AE, Wu LY, Qian DZ, Schedin P, et al. Identifying phenotype-associated subpopulations by integrating bulk and single-cell sequencing data. Nat Biotechnol. 2022;40(4):527\u201338.","journal-title":"Nat Biotechnol"},{"issue":"4","key":"637_CR43","doi-asserted-by":"publisher","first-page":"W461","DOI":"10.2214\/AJR.14.13139","volume":"204","author":"JR C\u00e2mara","year":"2015","unstructured":"C\u00e2mara JR, Keen JR, Asgarzadie F. Functional radiography in examination of spondylolisthesis. AJR Am J Roentgenol. 2015;204(4):W461-9.","journal-title":"AJR Am J Roentgenol"},{"issue":"11","key":"637_CR44","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.2106\/00004623-200211000-00008","volume":"84","author":"Y Yukawa","year":"2002","unstructured":"Yukawa Y, Lenke LG, Tenhula J, Bridwell KH, Riew KD, Blanke K. A comprehensive study of patients with surgically treated lumbar spinal stenosis with neurogenic claudication. J Bone Joint Surg Am. 2002;84(11):1954\u20139.","journal-title":"J Bone Joint Surg Am"},{"issue":"21","key":"637_CR45","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1097\/00007632-200111010-00004","volume":"26","author":"J Virri","year":"2001","unstructured":"Virri J, Gr\u00f6nblad M, Seitsalo S, Habtemariam A, K\u00e4\u00e4p\u00e4 E, Karaharju E. Comparison of the prevalence of inflammatory cells in subtypes of disc herniations and associations with straight leg raising. Spine. 2001;26(21):2311\u20135.","journal-title":"Spine"},{"key":"637_CR46","doi-asserted-by":"publisher","first-page":"108019","DOI":"10.1016\/j.compbiomed.2024.108019","volume":"170","author":"Z Xi","year":"2024","unstructured":"Xi Z, Xie Y, Sun S, Wang N, Chen S, Wang G, et al. IVD fibrosis and disc collapse comprehensively aggravate vertebral body disuse osteoporosis and zygapophyseal joint osteoarthritis by posteriorly shifting the load transmission pattern. Comput Biol Med. 2024;170:108019.","journal-title":"Comput Biol Med"},{"issue":"10","key":"637_CR47","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.molmed.2022.07.007","volume":"28","author":"G Li","year":"2022","unstructured":"Li G, Zhang W, Liang H, Yang C. Epigenetic regulation in intervertebral disc degeneration. Trends Mol Med. 2022;28(10):803\u20135.","journal-title":"Trends Mol Med"},{"issue":"1","key":"637_CR48","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s13018-025-05471-2","volume":"20","author":"Y Fu","year":"2025","unstructured":"Fu Y, Zhu L, Ma B. Mechanism of lncRNA ZFAS1 mediating nucleus pulposus cell pyroptosis in intervertebral disc degeneration. J Orthop Surg Res. 2025;20(1):198.","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"637_CR49","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.joca.2013.10.019","volume":"22","author":"M Teraguchi","year":"2014","unstructured":"Teraguchi M, Yoshimura N, Hashizume H, Muraki S, Yamada H, Minamide A, et al. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthritis Cartilage. 2014;22(1):104\u201310.","journal-title":"Osteoarthritis Cartilage"}],"container-title":["Military Medical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40779-025-00637-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40779-025-00637-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40779-025-00637-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T20:53:10Z","timestamp":1772830390000},"score":1,"resource":{"primary":{"URL":"https:\/\/mmrjournal.biomedcentral.com\/articles\/10.1186\/s40779-025-00637-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["637"],"URL":"https:\/\/doi.org\/10.1186\/s40779-025-00637-9","relation":{},"ISSN":["2054-9369"],"issn-type":[{"value":"2054-9369","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"assertion":[{"value":"15 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was performed in accordance to the Declaration of Helsinki and was approved by the Ethics Committee of the Army Medical Center of PLA (2022-312). The information of all patients was deidentified to protect patient privacy. Written informed consent for this study was obtained from all participants. This study was registered in the Chinese Clinical Trial Registry at\n                      \n                      (ChiCTR2200066854).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All the authors declare that they have no competing interests and that no generative AI or AI-assisted technology was employed in the writing process. The Army Medical Center of PLA supported this submission.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"54"}}