{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:24:54Z","timestamp":1792801494518,"version":"4.5.0"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W019418\/1"],"award-info":[{"award-number":["MR\/W019418\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W019418\/1"],"award-info":[{"award-number":["MR\/W019418\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M008959\/1"],"award-info":[{"award-number":["MR\/M008959\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M008959\/1"],"award-info":[{"award-number":["MR\/M008959\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W019418\/1"],"award-info":[{"award-number":["MR\/W019418\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W019418\/1"],"award-info":[{"award-number":["MR\/W019418\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ECMage Network","award":["E&M\/R1\/08"],"award-info":[{"award-number":["E&M\/R1\/08"]}]},{"name":"ECMage Network","award":["E&M\/R1\/08"],"award-info":[{"award-number":["E&M\/R1\/08"]}]},{"name":"ECMage Network","award":["E&M\/R1\/08"],"award-info":[{"award-number":["E&M\/R1\/08"]}]},{"name":"Faculty of Biology, Medicine and Health Research Development Award"},{"name":"RGC European Union - Hong Kong Research and Innovation Cooperation Co-funding Mechanism","award":["E-HKU703\/18"],"award-info":[{"award-number":["E-HKU703\/18"]}]},{"name":"Manchester Academic Health Science Centre","id":[{"id":"https:\/\/ror.org\/04rrkhs81","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intervertebral disc (IVD) degeneration is a common cause of low back pain, and the most symptomatic patients with neural compression need surgical intervention to relieve symptoms. Current techniques used to diagnose IVD degeneration, such as magnetic resonance imaging (MRI), do not detect changes in the tissue extracellular matrix (ECM) as degeneration progresses. Improved techniques, such as a combination of tissue and blood biomarkers, are needed to monitor the progression of IVD degeneration for more effective treatment plans.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To identify tissue and blood biomarkers associated with degeneration progression, we histologically graded 35 adult human degenerate IVD tissues and matched plasma from the individuals into two groups: mild degenerate and severe degenerate. Mass spectrometry was utilised to characterise proteomic differences in tissue and plasma between the two groups. Top differentially distributed proteins were further validated using immunohistochemistry and qRT-PCR. Additionally, correlational analyses were conducted to define similarities and differences between tissue and plasma protein changes in individuals with mild and severe IVD degeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our data revealed that the abundance of 31 proteins was significantly increased in severe degenerated IVD tissues compared to mild. Functional analyses showed that more than 40% of these proteins were matrisome-related, indicating differences in ECM protein composition between severe and mild degenerate IVD tissues. We confirmed adipocyte enhancer-binding protein 1 (AEBP1) as one of the most significantly enriched core matrisome genes and proteins as degeneration progressed. Compared to others, AEBP1 protein levels best distinguished between mild and severe degenerated IVD tissues with an area under the curve score of 0.768 (95% CI: 0.60\u20130.93). However, we found that protein changes from associated plasma exhibited a weak relationship with histological grading and AEBP1 tissue levels. Given that systemic plasma changes are complex, a larger sample cohort may be required to identify patterns in blood relating to IVD degeneration progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this study, we have identified AEBP1 as a tissue marker for monitoring the severity of disc degeneration in humans. Further work to link alterations in tissue AEBP1 levels to changes in blood-related proteins will be beneficial for detailed monitoring of IVD degeneration thereby enabling more personalised treatment approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-025-03489-9","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T02:01:06Z","timestamp":1739152866000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Proteomic profiling of human plasma and intervertebral disc tissue reveals matrisomal, but not plasma, biomarkers of disc degeneration"],"prefix":"10.1186","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8155-5793","authenticated-orcid":false,"given":"Christabel Thembela","family":"Dube","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-765X","authenticated-orcid":false,"given":"Hamish T. J.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"Rabbitte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Baird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-8494","authenticated-orcid":false,"given":"Jeremy A.","family":"Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivona","family":"Baricevic-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-9111","authenticated-orcid":false,"given":"Richard D.","family":"Unwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-5778","authenticated-orcid":false,"given":"Danny","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanna","family":"Gnanalingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4876-5208","authenticated-orcid":false,"given":"Judith A.","family":"Hoyland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-4135","authenticated-orcid":false,"given":"Stephen M.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"issue":"1","key":"3489_CR1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1111\/j.1533-2500.2007.00171.x","volume":"8","author":"PP Raj","year":"2008","unstructured":"Raj PP. Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract. 2008;8(1):18\u201344.","journal-title":"Pain Pract"},{"issue":"3","key":"3489_CR2","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.arr.2007.08.001","volume":"6","author":"C-Q Zhao","year":"2007","unstructured":"Zhao C-Q, Wang L-M, Jiang L-S, Dai L-Y. The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev. 2007;6(3):247\u201361.","journal-title":"Ageing Res Rev"},{"issue":"2","key":"3489_CR3","doi-asserted-by":"publisher","first-page":"42","DOI":"10.5312\/wjo.v4.i2.42","volume":"4","author":"BG Peng","year":"2013","unstructured":"Peng BG. Pathophysiology, diagnosis, and treatment of discogenic low back pain. World J Orthop. 2013;4(2):42\u201352.","journal-title":"World J Orthop"},{"key":"3489_CR4","doi-asserted-by":"crossref","unstructured":"Mallio CA, Vadal\u00e0 G, Russo F, Bernetti C, Ambrosio L, Zobel BB et al. Novel magnetic resonance imaging tools for the diagnosis of degenerative disc disease: a narrative review. Diagnostics (Basel). 2022;12(2).","DOI":"10.3390\/diagnostics12020420"},{"issue":"2","key":"3489_CR5","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1136\/mp.55.2.91","volume":"55","author":"JI Sive","year":"2002","unstructured":"Sive JI, Baird P, Jeziorsk M, Watkins A, Hoyland JA, Freemont AJ. Expression of chondrocyte markers by cells of normal and degenerate intervertebral discs. Mol Pathol. 2002;55(2):91\u20137.","journal-title":"Mol Pathol"},{"issue":"1","key":"3489_CR6","doi-asserted-by":"publisher","first-page":"6651","DOI":"10.1038\/s41598-021-85029-4","volume":"11","author":"Y Fan","year":"2021","unstructured":"Fan Y, Ren X, Liu X, Shi D, Xu E, Wang S, et al. Combined detection of CA15-3, CEA, and SF in serum and tissue of canine mammary gland tumor patients. Sci Rep. 2021;11(1):6651.","journal-title":"Sci Rep"},{"issue":"5","key":"3489_CR7","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1021\/ac902204k","volume":"82","author":"DJ Johann Jr","year":"2010","unstructured":"Johann DJ Jr., Wei BR, Prieto DA, Chan KC, Ye X, Valera VA, et al. Combined blood\/tissue analysis for cancer biomarker discovery: application to renal cell carcinoma. Anal Chem. 2010;82(5):1584\u20138.","journal-title":"Anal Chem"},{"issue":"10","key":"3489_CR8","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1097\/PHM.0000000000001943","volume":"101","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Yao L, Robinson KM, Dillingham TR. Biomarkers in the degenerative human intervertebral disc tissue and blood. Am J Phys Med Rehabil. 2022;101(10):983\u20137.","journal-title":"Am J Phys Med Rehabil"},{"issue":"1","key":"3489_CR9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13075-015-0887-8","volume":"18","author":"KT Weber","year":"2016","unstructured":"Weber KT, Alipui DO, Sison CP, Bloom O, Quraishi S, Overby MC, et al. Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases. Arthritis Res Therapy. 2016;18(1):3.","journal-title":"Arthritis Res Therapy"},{"issue":"1\u20133","key":"3489_CR10","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1007\/s12026-015-8709-2","volume":"63","author":"KT Weber","year":"2015","unstructured":"Weber KT, Satoh S, Alipui DO, Virojanapa J, Levine M, Sison C, et al. Exploratory study for identifying systemic biomarkers that correlate with pain response in patients with intervertebral disc disorders. Immunol Res. 2015;63(1\u20133):170\u201380.","journal-title":"Immunol Res"},{"key":"3489_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22203\/eCM.v031a01","volume":"31","author":"S Grad","year":"2016","unstructured":"Grad S, Bow C, Karppinen J, Luk KD, Cheung KM, Alini M, et al. Systemic blood plasma CCL5 and CXCL6: potential biomarkers for human lumbar disc degeneration. Eur Cell Mater. 2016;31:1\u201310.","journal-title":"Eur Cell Mater"},{"issue":"11","key":"3489_CR12","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1097\/BRS.0b013e318285ae08","volume":"38","author":"CK Kepler","year":"2013","unstructured":"Kepler CK, Markova DZ, Dibra F, Yadla S, Vaccaro AR, Risbud MV, et al. Expression and relationship of proinflammatory chemokine RANTES\/CCL5 and cytokine IL-1\u03b2 in painful human intervertebral discs. Spine (Phila Pa 1976). 2013;38(11):873\u201380.","journal-title":"Spine (Phila Pa 1976)"},{"issue":"15","key":"3489_CR13","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1016\/j.clinbiochem.2009.06.017","volume":"42","author":"S Lee","year":"2009","unstructured":"Lee S, Moon CS, Sul D, Lee J, Bae M, Hong Y, et al. Comparison of growth factor and cytokine expression in patients with degenerated disc disease and herniated nucleus pulposus. Clin Biochem. 2009;42(15):1504\u201311.","journal-title":"Clin Biochem"},{"issue":"4","key":"3489_CR14","doi-asserted-by":"publisher","first-page":"e1280","DOI":"10.1002\/jsp2.1280","volume":"6","author":"CL Pereira","year":"2023","unstructured":"Pereira CL, Grad S, Gon\u00e7alves RM. Biomarkers for intervertebral disc and associated back pain: from diagnosis to disease prognosis and personalized treatment. JOR SPINE. 2023;6(4):e1280.","journal-title":"JOR SPINE"},{"key":"3489_CR15","doi-asserted-by":"crossref","unstructured":"Kibble MJ, Domingos M, Hoyland JA, Richardson SM. Importance of matrix cues on intervertebral disc development, degeneration, and regeneration. Int J Mol Sci. 2022;23(13).","DOI":"10.3390\/ijms23136915"},{"key":"3489_CR16","doi-asserted-by":"publisher","first-page":"100036","DOI":"10.1016\/j.mbplus.2020.100036","volume":"6\u20137","author":"T Ohnishi","year":"2020","unstructured":"Ohnishi T, Novais EJ, Risbud MV. Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration. Matrix Biology Plus. 2020;6\u20137:100036.","journal-title":"Matrix Biology Plus"},{"issue":"12","key":"3489_CR17","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/nbt.1511","volume":"26","author":"J Cox","year":"2008","unstructured":"Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26(12):1367\u201372.","journal-title":"Nat Biotechnol"},{"issue":"12","key":"3489_CR18","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1038\/nprot.2016.136","volume":"11","author":"S Tyanova","year":"2016","unstructured":"Tyanova S, Temu T, Cox J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat Protoc. 2016;11(12):2301\u201319.","journal-title":"Nat Protoc"},{"issue":"9","key":"3489_CR19","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.1074\/mcp.M113.031591","volume":"13","author":"J Cox","year":"2014","unstructured":"Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteom. 2014;13(9):2513\u201326.","journal-title":"Mol Cell Proteom"},{"key":"3489_CR20","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: elegant graphics for data analysis","author":"H Wickham","year":"2016","unstructured":"Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer-; 2016."},{"key":"3489_CR21","unstructured":"EnhancedVolcano. Publication-ready volcano plots with enhanced colouring and labeling.. R package version 1.22.0,. 2024."},{"key":"3489_CR22","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128.","journal-title":"BMC Bioinformatics"},{"key":"3489_CR23","unstructured":"G Y, enrichplot. Visualization of functional enrichment result. R package version 1.24.2. 2024."},{"issue":"3","key":"3489_CR24","first-page":"100141","volume":"2","author":"T Wu","year":"2021","unstructured":"Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innov. 2021;2(3):100141.","journal-title":"Innov"},{"key":"3489_CR25","doi-asserted-by":"crossref","unstructured":"Naba A, Clauser KR, Hoersch S, Liu H, Carr SA, Hynes RO. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices molecular & cellular proteomics. 2012;11(4).","DOI":"10.1074\/mcp.M111.014647"},{"issue":"7","key":"3489_CR26","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.1093\/bioinformatics\/btz898","volume":"36","author":"KA McGurk","year":"2020","unstructured":"McGurk KA, Dagliati A, Chiasserini D, Lee D, Plant D, Baricevic-Jones I, et al. The use of missing values in proteomic data-independent acquisition mass spectrometry to enable disease activity discrimination. Bioinformatics. 2020;36(7):2217\u201323.","journal-title":"Bioinformatics"},{"issue":"1","key":"3489_CR27","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","volume":"17","author":"V Demichev","year":"2020","unstructured":"Demichev V, Messner CB, Vernardis SI, Lilley KS, Ralser M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat Methods. 2020;17(1):41\u20134.","journal-title":"Nat Methods"},{"key":"3489_CR28","doi-asserted-by":"crossref","unstructured":"Hsiao Y, Zhang H, Li GX, Deng Y, Yu F, Kahrood HV et al. Analysis and visualization of quantitative proteomics data using FragPipe-Analyst. bioRxiv. 2024.","DOI":"10.1101\/2024.03.05.583643"},{"issue":"7","key":"3489_CR29","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":"1","key":"3489_CR30","doi-asserted-by":"publisher","first-page":"e1312","DOI":"10.1002\/jsp2.1312","volume":"7","author":"I Heggli","year":"2024","unstructured":"Heggli I, Teixeira GQ, Iatridis JC, Neidlinger-Wilke C, Dudli S. The role of the complement system in disc degeneration and Modic changes. JOR Spine. 2024;7(1):e1312.","journal-title":"JOR Spine"},{"key":"3489_CR31","doi-asserted-by":"crossref","unstructured":"Cherif H, Mannarino M, Pacis AS, Ragoussis J, Rabau O, Ouellet JA et al. Single-cell RNA-Seq analysis of cells from degenerating and non-degenerating intervertebral discs from the same individual reveals new biomarkers for intervertebral disc degeneration. Int J Mol Sci. 2022;23(7).","DOI":"10.3390\/ijms23073993"},{"issue":"1","key":"3489_CR32","doi-asserted-by":"publisher","first-page":"e1323","DOI":"10.1002\/jsp2.1323","volume":"7","author":"R Compte","year":"2024","unstructured":"Compte R, Freidin MB, Granville Smith I, Le Maitre CL, Vaitkute D, Nessa A, et al. No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins. JOR SPINE. 2024;7(1):e1323.","journal-title":"JOR SPINE"},{"issue":"1","key":"3489_CR33","doi-asserted-by":"publisher","first-page":"e1237","DOI":"10.1002\/jsp2.1237","volume":"6","author":"I Heggli","year":"2023","unstructured":"Heggli I, Laux CJ, Mengis T, Karol A, Cornaz F, Herger N, et al. Modic type 2 changes are fibroinflammatory changes with complement system involvement adjacent to degenerated vertebral endplates. JOR Spine. 2023;6(1):e1237.","journal-title":"JOR Spine"},{"key":"3489_CR34","doi-asserted-by":"crossref","unstructured":"Yang X, Lu Y, Zhou H, Jiang H-T, 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 Biology. 2023;11.","DOI":"10.3389\/fcell.2023.1136777"},{"key":"3489_CR35","doi-asserted-by":"crossref","unstructured":"Nayagam SM, Ramachandran K, Selvaraj G, Sunmathi R, Easwaran M, Palraj ND, et al. Identification of extracellular matrix proteins in plasma as a potential biomarker for intervertebral disc degeneration. Eur Spine J. 2024;33(11):4062\u201375.","DOI":"10.1007\/s00586-024-08481-6"},{"issue":"8","key":"3489_CR36","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.spinee.2021.04.015","volume":"21","author":"FC Bonnaire","year":"2021","unstructured":"Bonnaire FC, Danalache M, Sigwart VA, Breuer W, Rolauffs B, Hofmann UK. The intervertebral disc from embryonic development to disc degeneration: insights into spatial cellular organization. Spine J. 2021;21(8):1387\u201398.","journal-title":"Spine J"},{"issue":"3","key":"3489_CR37","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3109\/03008200109005650","volume":"42","author":"WE Johnson","year":"2001","unstructured":"Johnson WE, Eisenstein SM, Roberts S. Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connect Tissue Res. 2001;42(3):197\u2013207.","journal-title":"Connect Tissue Res"},{"issue":"3","key":"3489_CR38","doi-asserted-by":"publisher","first-page":"382","DOI":"10.5115\/acb.23.067","volume":"56","author":"P Lama","year":"2023","unstructured":"Lama P, Tiwari J, Mutreja P, Chauhan S, Harding IJ, Dolan T, et al. Cell clusters in intervertebral disc degeneration: an attempted repair mechanism aborted via apoptosis. Anat Cell Biol. 2023;56(3):382\u201393.","journal-title":"Anat Cell Biol"},{"key":"3489_CR39","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.matbio.2018.03.024","volume":"70","author":"Y Zhang","year":"2018","unstructured":"Zhang Y, Xiong C, Kudelko M, Li Y, Wang C, Wong YL, et al. Early onset of disc degeneration in SM\/J mice is associated with changes in ion transport systems and fibrotic events. Matrix Biol. 2018;70:123\u201339.","journal-title":"Matrix Biol"},{"issue":"7","key":"3489_CR40","doi-asserted-by":"publisher","first-page":"e0219764","DOI":"10.1371\/journal.pone.0219764","volume":"14","author":"GS Gerhard","year":"2019","unstructured":"Gerhard GS, Hanson A, Wilhelmsen D, Piras IS, Still CD, Chu X, et al. AEBP1 expression increases with severity of fibrosis in NASH and is regulated by glucose, palmitate, and miR-372-3p. PLoS ONE. 2019;14(7):e0219764.","journal-title":"PLoS ONE"},{"key":"3489_CR41","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1097\/00007632-200011010-00005","volume":"25","author":"TR Oegema Jr","year":"2000","unstructured":"Oegema TR Jr., Johnson SL, Aguiar DJ, Ogilvie JW. Fibronectin and its fragments increase with degeneration in the human intervertebral disc. Spine. 2000;25:21.","journal-title":"Spine"},{"issue":"1","key":"3489_CR42","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13075-021-02690-w","volume":"24","author":"AL Castro","year":"2022","unstructured":"Castro AL, Ribeiro-Machado C, Oliveira CM, Teixeira GQ, Neidlinger-Wilke C, Pereira P, et al. Fibrotic alterations in human annulus fibrosus correlate with progression of intervertebral disc herniation. Arthritis Res Ther. 2022;24(1):25.","journal-title":"Arthritis Res Ther"},{"issue":"1","key":"3489_CR43","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/S0378-1119(01)00771-5","volume":"280","author":"H-S Ro","year":"2001","unstructured":"Ro H-S, Kim S-W, Wu D, Webber C, Nicholson TE. Gene structure and expression of the mouse adipocyte enhancer-binding protein. Gene. 2001;280(1):123\u201333.","journal-title":"Gene"},{"issue":"4","key":"3489_CR44","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.ajhg.2018.02.018","volume":"102","author":"PR Blackburn","year":"2018","unstructured":"Blackburn PR, Xu Z, Tumelty KE, Zhao RW, Monis WJ, Harris KG, et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am J Hum Genet. 2018;102(4):696\u2013705.","journal-title":"Am J Hum Genet"},{"issue":"25","key":"3489_CR45","doi-asserted-by":"publisher","first-page":"15654","DOI":"10.1074\/jbc.273.25.15654","volume":"273","author":"MD Layne","year":"1998","unstructured":"Layne MD, Endege WO, Jain MK, Yet S-F, Hsieh C-M, Chin MT, et al. Aortic carboxypeptidase-like protein, a novel protein with discoidin and carboxypeptidase-like domains, is up-regulated during vascular smooth muscle cell differentiation *. J Biol Chem. 1998;273(25):15654\u201360.","journal-title":"J Biol Chem"},{"key":"3489_CR46","doi-asserted-by":"crossref","unstructured":"Tam V, Chen P, Yee A, Solis N, Klein T, Kudelko M et al. DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics. Elife. 2020;9.","DOI":"10.7554\/eLife.64940"},{"issue":"15","key":"3489_CR47","doi-asserted-by":"publisher","first-page":"5256","DOI":"10.1128\/MCB.21.15.5256-5261.2001","volume":"21","author":"MD Layne","year":"2001","unstructured":"Layne MD, Yet S-F, Maemura K, Hsieh C-M, Bernfield M, Perrella MA, et al. Impaired abdominal wall development and deficient wound healing in mice lacking aortic carboxypeptidase-like protein. Mol Cell Biol. 2001;21(15):5256\u201361.","journal-title":"Mol Cell Biol"},{"issue":"3","key":"3489_CR48","doi-asserted-by":"publisher","first-page":"818","DOI":"10.2353\/ajpath.2009.080856","volume":"174","author":"SL Schissel","year":"2009","unstructured":"Schissel SL, Dunsmore SE, Liu X, Shine RW, Perrella MA, Layne MD. Aortic carboxypeptidase-like protein is expressed in fibrotic human lung and its absence protects against bleomycin-induced lung fibrosis. Am J Pathol. 2009;174(3):818\u201328.","journal-title":"Am J Pathol"},{"issue":"2","key":"3489_CR49","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1006\/bbrc.1996.1675","volume":"228","author":"I Ohno","year":"1996","unstructured":"Ohno I, Hashimoto J, Shimizu K, Takaoka K, Ochi T, Matsubara K, et al. A cDNA cloning of human AEBP1 from primary cultured osteoblasts and its expression in a differentiating osteoblastic cell line. Biochem Biophys Res Commun. 1996;228(2):411\u20134.","journal-title":"Biochem Biophys Res Commun"},{"issue":"6552","key":"3489_CR50","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/378092a0","volume":"378","author":"G-P He","year":"1995","unstructured":"He G-P, Muise A, Li AW, Ro H-S. A eukaryotic transcriptional represser with carboxypeptidase activity. Nature. 1995;378(6552):92\u20136.","journal-title":"Nature"},{"issue":"9","key":"3489_CR51","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1302\/2046-3758.129.BJR-2022-0369.R2","volume":"12","author":"G-Z Zhang","year":"2023","unstructured":"Zhang G-Z, Li L, Luo Z-B, Zhang C-Y, Wang Y-G, Kang X-W. Identification and experimental validation of key extracellular proteins as potential targets in intervertebral disc degeneration. Bone Joint Res. 2023;12(9):522\u201335.","journal-title":"Bone Joint Res"},{"issue":"2","key":"3489_CR52","doi-asserted-by":"publisher","first-page":"e12022","DOI":"10.1002\/ccs3.12022","volume":"18","author":"L Cao","year":"2024","unstructured":"Cao L, Gao W, Yang H, Zeng R, Yin Z. Adipocyte enhancer binding protein 1 knockdown alleviates osteoarthritis through inhibiting NF-\u03baB signaling pathway-mediated inflammation and extracellular matrix degradation. J Cell Commun Signal. 2024;18(2):e12022.","journal-title":"J Cell Commun Signal"},{"issue":"4","key":"3489_CR53","doi-asserted-by":"publisher","first-page":"e1123","DOI":"10.1002\/jsp2.1123","volume":"3","author":"DE Fournier","year":"2020","unstructured":"Fournier DE, Kiser PK, Shoemaker JK, Batti\u00e9 MC, S\u00e9guin CA. Vascularization of the human intervertebral disc: a scoping review. JOR SPINE. 2020;3(4):e1123.","journal-title":"JOR SPINE"},{"issue":"11","key":"3489_CR54","doi-asserted-by":"publisher","first-page":"2474","DOI":"10.1007\/s00586-013-2842-1","volume":"22","author":"T R\u00e4tsep","year":"2013","unstructured":"R\u00e4tsep T, Minajeva A, Asser T. Relationship between neovascularization and degenerative changes in herniated lumbar intervertebral discs. Eur Spine J. 2013;22(11):2474\u201380.","journal-title":"Eur Spine J"},{"issue":"8","key":"3489_CR55","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1097\/00007632-199904150-00002","volume":"24","author":"RR Pai","year":"1999","unstructured":"Pai RR, D\u2019sa B, Raghuveer CV, Kamath A. Neovascularization of nucleus pulposus. A diagnostic feature of intervertebral disc prolapse. Spine (Phila Pa 1976). 1999;24(8):739\u201341.","journal-title":"Spine (Phila Pa 1976)"},{"issue":"1","key":"3489_CR56","doi-asserted-by":"publisher","first-page":"3948","DOI":"10.1038\/s41598-021-82941-7","volume":"11","author":"D Wang","year":"2021","unstructured":"Wang D, Rabhi N, Yet S-F, Farmer SR, Layne MD. Aortic carboxypeptidase-like protein regulates vascular adventitial progenitor and fibroblast differentiation through myocardin related transcription factor A. Sci Rep. 2021;11(1):3948.","journal-title":"Sci Rep"},{"issue":"5","key":"3489_CR57","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1111\/cas.14360","volume":"111","author":"A Yorozu","year":"2020","unstructured":"Yorozu A, Yamamoto E, Niinuma T, Tsuyada A, Maruyama R, Kitajima H, et al. Upregulation of adipocyte enhancer-binding protein 1 in endothelial cells promotes tumor angiogenesis in colorectal cancer. Cancer Sci. 2020;111(5):1631\u201344.","journal-title":"Cancer Sci"},{"issue":"1","key":"3489_CR58","doi-asserted-by":"publisher","first-page":"e16712","DOI":"10.1371\/journal.pone.0016712","volume":"6","author":"X Liu","year":"2011","unstructured":"Liu X, Lin Z, Zhou T, Zong R, He H, Liu Z, et al. Anti-angiogenic and anti-inflammatory effects of SERPINA3K on corneal injury. PLoS ONE. 2011;6(1):e16712.","journal-title":"PLoS ONE"},{"key":"3489_CR59","doi-asserted-by":"crossref","unstructured":"Lin TY, Yang CH, Chou HC, Cheng CM, Liu YW, Wang JY et al. EGFR mutation-harboring lung cancer cells produce CLEC11A with endothelial trophic and tumor-promoting activities. Cancers (Basel). 2022;14(5).","DOI":"10.3390\/cancers14051356"},{"issue":"1","key":"3489_CR60","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.yexcr.2017.02.011","volume":"352","author":"Q Xie","year":"2017","unstructured":"Xie Q, Xie J, Tian T, Ma Q, Zhang Q, Zhu B, et al. Hypoxia triggers angiogenesis by increasing expression of LOX genes in 3-D culture of ASCs and ECs. Exp Cell Res. 2017;352(1):157\u201363.","journal-title":"Exp Cell Res"},{"issue":"11","key":"3489_CR61","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1002\/bjs.4275","volume":"90","author":"TA Drixler","year":"2003","unstructured":"Drixler TA, Vogten JM, Gebbink MFBG, Carmeliet P, Voest EE, Borel Rinkes IHM. Plasminogen mediates liver regeneration and angiogenesis after experimental partial hepatectomy. Br J Surg. 2003;90(11):1384\u201390.","journal-title":"Br J Surg"},{"issue":"2","key":"3489_CR62","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.gendis.2020.07.015","volume":"9","author":"Y Pan","year":"2022","unstructured":"Pan Y, Deng L, Wang H, He K, Xia Q. Histidine-rich glycoprotein (HRGP): pleiotropic and paradoxical effects on macrophage, tumor microenvironment, angiogenesis, and other physiological and pathological processes. Genes Dis. 2022;9(2):381\u201392.","journal-title":"Genes Dis"},{"issue":"22","key":"3489_CR63","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.21037\/atm-21-5183","volume":"9","author":"M Liu","year":"2021","unstructured":"Liu M, Yu Y, Zhang Z, Chen Z, Chen B, Cheng Y, et al. AEBP1 as a potential immune-related prognostic biomarker in glioblastoma: a bioinformatic analyses. Ann Transl Med. 2021;9(22):1657.","journal-title":"Ann Transl Med"},{"issue":"1","key":"3489_CR64","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.spinee.2021.07.003","volume":"22","author":"S Rajasekaran","year":"2022","unstructured":"Rajasekaran S, Soundararajan DCR, Nayagam SM, Tangavel C, Raveendran M, Thippeswamy PB, et al. Modic changes are associated with activation of intense inflammatory and host defense response pathways \u2013 molecular insights from proteomic analysis of human intervertebral discs. Spine J. 2022;22(1):19\u201338.","journal-title":"Spine J"},{"issue":"2","key":"3489_CR65","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1097\/00007632-200301150-00004","volume":"28","author":"M Gr\u00f6nblad","year":"2003","unstructured":"Gr\u00f6nblad M, Habtemariam A, Virri J, Seitsalo S, Vanharanta H, Guyer RD. Complement membrane attack complexes in pathologic disc tissues. Spine (Phila Pa 1976). 2003;28(2):114\u20138.","journal-title":"Spine (Phila Pa 1976)"},{"key":"3489_CR66","doi-asserted-by":"crossref","unstructured":"Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proceedings of the National Academy of Sciences. 2006;103(7):2328-33.","DOI":"10.1073\/pnas.0408835103"},{"issue":"4","key":"3489_CR67","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/sj.cdd.4400826","volume":"8","author":"US Gaipl","year":"2001","unstructured":"Gaipl US, Kuenkele S, Voll RE, Beyer TD, Kolowos W, Heyder P, et al. Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ. 2001;8(4):327\u201334.","journal-title":"Cell Death Differ"},{"issue":"12","key":"3489_CR68","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1084\/jem.188.12.2313","volume":"188","author":"D Mevorach","year":"1998","unstructured":"Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188(12):2313\u201320.","journal-title":"J Exp Med"},{"issue":"7","key":"3489_CR69","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1097\/00007632-199804010-00001","volume":"23","author":"HE Gruber","year":"1998","unstructured":"Gruber HE, Hanley ENJ. Analysis of aging and degeneration of the human intervertebral disc: comparison of surgical specimens with normal controls. Spine. 1998;23(7):751\u20137.","journal-title":"Spine"},{"issue":"20","key":"3489_CR70","doi-asserted-by":"publisher","first-page":"e2118510119","DOI":"10.1073\/pnas.2118510119","volume":"119","author":"S McHarg","year":"2022","unstructured":"McHarg S, Booth L, Perveen R, Riba Garcia I, Brace N, Bayatti N, et al. Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. Proc Natl Acad Sci. 2022;119(20):e2118510119.","journal-title":"Proc Natl Acad Sci"},{"issue":"2","key":"3489_CR71","doi-asserted-by":"publisher","first-page":"206","DOI":"10.5937\/jomb0-39557","volume":"42","author":"Y Chen","year":"2023","unstructured":"Chen Y, Wei H, Xu F. Antioxidative behavior of a2-macroglobulin in intervertebral disc degeneration. J Med Biochem. 2023;42(2):206\u201313.","journal-title":"J Med Biochem"},{"issue":"1","key":"3489_CR72","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/jor.25348","volume":"41","author":"C Sun","year":"2023","unstructured":"Sun C, Cao C, Zhao T, Guo H, Fleming BC, Owens B, et al. A2M inhibits inflammatory mediators of chondrocytes by blocking IL-1\u03b2\/NF-\u03baB pathway. J Orthop Res. 2023;41(1):241\u20138.","journal-title":"J Orthop Res"},{"key":"3489_CR73","doi-asserted-by":"crossref","unstructured":"Pasquale XM, Jason MC, Gaetano JS. Intradiscal injection of an autologous alpha-2-macroglobulin (A2M) concentrate alleviates back pain in FAC-positive patients. Orthop Rheumatol Open Access J. 2017;4.","DOI":"10.19080\/OROAJ.2016.04.555634"},{"key":"3489_CR74","doi-asserted-by":"crossref","unstructured":"Coquelet P, Da Cal S, El Hage G, Tastet O, Balthazard R, Chaumont H, et al. Specific plasma biomarker signatures associated with patients undergoing surgery for back pain. Spine J. 2025;25(1):32\u201344.","DOI":"10.1016\/j.spinee.2024.09.002"},{"issue":"3","key":"3489_CR75","doi-asserted-by":"publisher","first-page":"e1337","DOI":"10.1002\/jsp2.1337","volume":"7","author":"F Schulze","year":"2024","unstructured":"Schulze F, M\u00e4\u00e4tt\u00e4 J, Grad S, Heggli I, Brunner F, Farshad M, et al. Proteomic analysis of serum in a population-based cohort did not reveal a biomarker for Modic changes. JOR SPINE. 2024;7(3):e1337.","journal-title":"JOR SPINE"},{"issue":"D1","key":"3489_CR76","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","volume":"50","author":"Y Perez-Riverol","year":"2022","unstructured":"Perez-Riverol Y, Bai J, Bandla C, Garc\u00eda-Seisdedos D, Hewapathirana S, Kamatchinathan S, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022;50(D1):D543\u201352.","journal-title":"Nucleic Acids Res"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-025-03489-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-025-03489-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-025-03489-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T02:42:30Z","timestamp":1739155350000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-025-03489-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":76,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3489"],"URL":"https:\/\/doi.org\/10.1186\/s13075-025-03489-9","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,10]]},"assertion":[{"value":"18 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 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":"All donors provided full written informed consent before tissue collection. This study was reviewed and approved by the National Research Ethics Service Committee North West (REC reference: 17\/LO\/1408).","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":"RDU is a founder and shareholder of Complement Therapeutics Inc (CTx), which is developing complement-targeted therapies initially in ocular disease. CTx played no role in the design, execution or analysis of this study. The remaining authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"28"}}