{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:19:12Z","timestamp":1774603152429,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","award":["cstc2021jcyj-msxmX0134"],"award-info":[{"award-number":["cstc2021jcyj-msxmX0134"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Low back pain (LBP) is a prevalent health problem worldwide that affects over 80% of adults during their lifetime. Intervertebral disc degeneration (IDD) is a well-recognized leading cause of LBP. IDD is classified into five grades according to the Pfirrmann classification system. The purpose of this study was to identify potential biomarkers in different IDD grades through an integrated analysis of proteome sequencing (PRO-seq), bulk RNA sequencing (bRNA-seq) and single-cell RNA sequencing (scRNA-seq) data. Eight cases of grade I-IV IDD were obtained. Grades I and II were considered non-degenerative discs (relatively normal), whereas grades III and IV were considered degenerative discs. PRO-seq analysis was performed to identify differentially expressed proteins (DEPs) in various IDD grades. Variation analysis was performed on bRNA-seq data to differentiate expressed genes (DEGs) in normal and degenerated discs. In addition, scRNA-seq was performed to validate DEGs in degenerated and non-degenerated nucleus pulposus (NP). Machine learning (ML) algorithms were used to screen hub genes. The receiver operating characteristic (ROC) curve was used to validate the efficiency of the screened hub genes to predict IDD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze function enrichment and signaling pathways. Protein-protein interaction (PPI) network was used to prioritize disease-related proteins. SERPINA1, ORM2, FGG and COL1A1 were identified through PRO-seq as the hub proteins involved in regulating IDD. ML algorithms selected ten hub genes, including IBSP, COL6A2, MMP2, SERPINA1, ACAN, FBLN7, LAMB2, TTLL7, COL9A3, and THBS4 in bRNA-seq. Since serine protease inhibitor clade A member 1 (SERPINA1) was the only common gene, its accuracy in degenerated and non-degenerated NP cells was validated using scRNA-seq. Then, the rat degeneration model of caudal vertebra was established. The expression of SERPINA1 and ORM2 was detected using immunohistochemical staining of human and rat intervertebral discs. The results showed that SERPINA1 was poorly expressed in the degenerative group. We further explored the potential function of SERPINA1 by Gene Set Enrichment Analysis (GSEA) and cell-cell communication. Therefore, SERPINA1 can be used as a biomarker to regulate or predict the progress of disc degeneration.<\/jats:p>","DOI":"10.3389\/fcell.2023.1136777","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T06:35:06Z","timestamp":1678948506000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Integrated proteome sequencing, bulk RNA sequencing and single-cell RNA sequencing to identify potential biomarkers in different grades of intervertebral disc degeneration"],"prefix":"10.3389","volume":"11","author":[{"given":"Xiao","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Tao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.rdc.2020.12.001","article-title":"Low back pain in adolescent and geriatric populations","volume":"47","author":"Borenstein","year":"2021","journal-title":"Rheumatic Dis. Clin. N. Am."},{"key":"B2","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/978-94-007-7893-1_12","article-title":"Collagen type VI myopathies","volume":"802","author":"Bushby","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.3390\/ijms21103601","article-title":"MicroRNAs in intervertebral disc degeneration, apoptosis, inflammation, and mechanobiology","volume":"21","author":"Cazzanelli","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.joca.2021.02.204","article-title":"Roles of NLRP3 inflammasome in intervertebral disc degeneration","volume":"29","author":"Chao-Yang","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e52570","DOI":"10.7554\/eLife.52570","article-title":"p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle","volume":"9","author":"Che","year":"2020","journal-title":"Elife"},{"key":"B6","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1136\/annrheumdis-2017-212056","article-title":"Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein","volume":"77","author":"Cheng","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.3390\/ijms23073993","article-title":"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","volume":"23","author":"Cherif","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e1146","DOI":"10.1002\/jsp2.1146","article-title":"Transcriptional profiling of intervertebral disc in a post-traumatic early degeneration organ culture model","volume":"4","author":"Cui","year":"2021","journal-title":"JOR spine"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/j.ajhg.2017.11.006","article-title":"ACTB loss-of-function mutations result in a pleiotropic developmental disorder","volume":"101","author":"Cuvertino","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B10","first-page":"154","article-title":"Angiogenesis in the degeneration of the lumbar intervertebral disc","volume":"3","author":"David","year":"2010","journal-title":"J. Med. Life"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1161\/CIRCULATIONAHA.115.001593","article-title":"Machine learning in medicine","volume":"132","author":"Deo","year":"2015","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"S46","DOI":"10.1093\/neuros\/nyw078","article-title":"Intervertebral disk degeneration and repair","volume":"80","author":"Dowdell","year":"2017","journal-title":"Neurosurgery"},{"key":"B13","doi-asserted-by":"publisher","first-page":"15263","DOI":"10.1038\/s41598-020-72261-7","article-title":"Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells","volume":"10","author":"Fernandes","year":"2020","journal-title":"Sci. Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"196","DOI":"10.22203\/eCM.v042a15","article-title":"Intervertebral disc decellularisation: Progress and challenges","volume":"42","author":"Fiordalisi","year":"2021","journal-title":"Eur. cells Mater."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1097\/BRS.0b013e3180bc2431","article-title":"Surgical interventions for lumbar disc prolapse: Updated cochrane review","volume":"32","author":"Gibson","year":"2007","journal-title":"Spine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/S0736-0266(00)00072-3","article-title":"Morphologic and molecular evidence for gap junctions and connexin 43 and 45 expression in annulus fibrosus cells from the human intervertebral disc","volume":"19","author":"Gruber","year":"2001","journal-title":"J. Orthop. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e827","DOI":"10.1097\/ccm.0000000000001707","article-title":"Fibrinogen \u03b3-chain peptide-coated adenosine 5' diphosphate-encapsulated liposomes rescue mice from lethal blast lung injury via adenosine signaling","volume":"44","author":"Hagisawa","year":"2016","journal-title":"Crit. care Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3186","DOI":"10.1111\/trf.15427","article-title":"Combination therapy using fibrinogen \u03b3-chain peptide-coated, ADP-encapsulated liposomes and hemoglobin vesicles for trauma-induced massive hemorrhage in thrombocytopenic rabbits","volume":"59","author":"Hagisawa","year":"2019","journal-title":"Transfusion"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2356","DOI":"10.1016\/s0140-6736(18)30480-x","article-title":"What low back pain is and why we need to pay attention","volume":"391","author":"Hartvigsen","year":"2018","journal-title":"Lancet (London, Engl."},{"key":"B20","doi-asserted-by":"publisher","first-page":"841831","DOI":"10.3389\/fcell.2022.841831","article-title":"Development, pathogenesis, and regeneration of the intervertebral disc: Current and future insights spanning traditional to omics methods","volume":"10","author":"Hickman","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1002\/art.34347","article-title":"A systematic review of the global prevalence of low back pain","volume":"64","author":"Hoy","year":"2012","journal-title":"Arthritis rheumatism"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1523\/jneurosci.2534-16.2017","article-title":"Astrocytic orosomucoid-2 modulates microglial activation and neuroinflammation","volume":"37","author":"Jo","year":"2017","journal-title":"J. Soc. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"15662","DOI":"10.1038\/srep15662","article-title":"Gene expression profiling identifies interferon signalling molecules and IGFBP3 in human degenerative annulus fibrosus","volume":"5","author":"Kazezian","year":"2015","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1042\/bst0350683","article-title":"F-actin cytoskeletal organization in intervertebral disc health and disease","volume":"35","author":"Li","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"B25","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jot.2020.07.007","article-title":"Identification of circ-FAM169A sponges miR-583 involved in the regulation of intervertebral disc degeneration","volume":"26","author":"Li","year":"2021","journal-title":"J. Orthop. Transl."},{"key":"B26","doi-asserted-by":"publisher","first-page":"910626","DOI":"10.3389\/fcell.2022.910626","article-title":"Single-cell RNA sequencing reveals the difference in human normal and degenerative nucleus pulposus tissue profiles and cellular interactions","volume":"10","author":"Li","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1097\/01.brs.0000259225.37454.38","article-title":"Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain","volume":"32","author":"Mirza","year":"2007","journal-title":"Spine"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e15796","DOI":"10.1097\/md.0000000000015796","article-title":"KEGG-expressed genes and pathways in intervertebral disc degeneration: Protocol for a systematic review and data mining","volume":"98","author":"Mo","year":"2019","journal-title":"Medicine"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1658","DOI":"10.1002\/wrna.1658","article-title":"Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny","volume":"12","author":"Morris","year":"2021","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6444","DOI":"10.18632\/oncotarget.27269","article-title":"Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients","volume":"10","author":"Neto","year":"2019","journal-title":"Oncotarget"},{"key":"B31","doi-asserted-by":"publisher","first-page":"112217","DOI":"10.1016\/j.yexcr.2020.112217","article-title":"SERPINA1 modulates expression of amyloidogenic transthyretin","volume":"395","author":"Niemietz","year":"2020","journal-title":"Exp. Cell Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","article-title":"The PRIDE database resources in 2022: A hub for mass spectrometry-based proteomics evidences","volume":"50","author":"Perez-Riverol","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1097\/00007632-200109010-00011","article-title":"Magnetic resonance classification of lumbar intervertebral disc degeneration","volume":"26","author":"Pfirrmann","year":"2001","journal-title":"Spine"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22203\/ecm.v010a01","article-title":"The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage","volume":"11","author":"Roughley","year":"2006","journal-title":"Eur. cells Mater."},{"key":"B35","doi-asserted-by":"publisher","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":"B36","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/s0016-5085(98)70642-0","article-title":"Collagens in the liver extracellular matrix bind hepatocyte growth factor","volume":"114","author":"Schuppan","year":"1998","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s00586-005-0988-1","article-title":"Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms","volume":"15","author":"Solovieva","year":"2006","journal-title":"Eur. spine J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"914","DOI":"10.3390\/ijms21030914","article-title":"SERPINA1 peptides in urine as A potential marker of preeclampsia severity","volume":"21","author":"Starodubtseva","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1080\/15548627.2020.1822097","article-title":"Mitophagy in degenerative joint diseases","volume":"17","author":"Sun","year":"2021","journal-title":"Autophagy"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.3390\/biom11091279","article-title":"The role of polymorphisms in collagen-encoding genes in intervertebral disc degeneration","volume":"11","author":"Trefilova","year":"2021","journal-title":"Biomolecules"},{"key":"B41","doi-asserted-by":"publisher","first-page":"12017","DOI":"10.1038\/s41598-020-68351-1","article-title":"Avidin grafted dextran nanostructure enables a month-long intra-discal retention","volume":"10","author":"Wagner","year":"2020","journal-title":"Sci. Rep."},{"key":"B42","doi-asserted-by":"publisher","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. chimica acta; Int. J. Clin. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"110660","DOI":"10.1016\/j.biopha.2020.110660","article-title":"The role of IL-1\u03b2 and TNF-\u03b1 in intervertebral disc degeneration","volume":"131","author":"Wang","year":"2020","journal-title":"Biomed. Pharmacother. = Biomedecine Pharmacother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.bbrc.2021.01.057","article-title":"ACTG1 regulates intervertebral disc degeneration via the NF-\u03baB-p65 and Akt pathways","volume":"545","author":"Wu","year":"","journal-title":"Biochem. biophysical Res. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jot.2021.04.003","article-title":"Kruppel like factor 10 prevents intervertebral disc degeneration via TGF-beta signaling pathway both in vitro and in vivo","volume":"29","author":"Wu","year":"","journal-title":"J. Orthop. Transl."},{"key":"B46","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1186\/s13018-021-02724-8","article-title":"Association between polymorphisms of collagen genes and susceptibility to intervertebral disc degeneration: A meta-analysis","volume":"16","author":"Xie","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"100978","DOI":"10.1016\/j.arr.2019.100978","article-title":"Intervertebral disc ageing and degeneration: The antiapoptotic effect of oestrogen","volume":"57","author":"Yang","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e1129","DOI":"10.1002\/jsp2.1129","article-title":"Spatial mapping of collagen content and structure in human intervertebral disk degeneration","volume":"3","author":"Zeldin","year":"2020","journal-title":"JOR Spine"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1016\/j.joca.2021.06.010","article-title":"Single-cell RNA-seq analysis identifies unique chondrocyte subsets and reveals involvement of ferroptosis in human intervertebral disc degeneration","volume":"29","author":"Zhang","year":"","journal-title":"Osteoarthr. Cartil."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e13057","DOI":"10.1111\/cpr.13057","article-title":"NF-\u03baB signalling pathways in nucleus pulposus cell function and intervertebral disc degeneration","volume":"54","author":"Zhang","year":"","journal-title":"Cell Prolif."},{"key":"B51","doi-asserted-by":"publisher","first-page":"804","DOI":"10.3748\/wjg.v26.i8.804","article-title":"Downregulation of orosomucoid 2 acts as a prognostic factor associated with cancer-promoting pathways in liver cancer","volume":"26","author":"Zhu","year":"2020","journal-title":"World J. gastroenterology"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1136777\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T06:35:11Z","timestamp":1678948511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1136777\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,16]]},"references-count":51,"alternative-id":["10.3389\/fcell.2023.1136777"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2023.1136777","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,16]]},"article-number":"1136777"}}