{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:20Z","timestamp":1787028560614,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T00:00:00Z","timestamp":1743292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"90th Anniversary of Chulalongkorn University, Ratchadaphisek Somphot Fund","award":["HEA_FF_68_088_3000_014"],"award-info":[{"award-number":["HEA_FF_68_088_3000_014"]}]},{"name":"90th Anniversary of Chulalongkorn University, Ratchadaphisek Somphot Fund","award":["CE67_113_3000_042"],"award-info":[{"award-number":["CE67_113_3000_042"]}]},{"DOI":"10.13039\/501100002873","name":"Center of Excellence in Osteoarthritis and Musculoskeleton","doi-asserted-by":"publisher","award":["HEA_FF_68_088_3000_014"],"award-info":[{"award-number":["HEA_FF_68_088_3000_014"]}],"id":[{"id":"10.13039\/501100002873","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002873","name":"Center of Excellence in Osteoarthritis and Musculoskeleton","doi-asserted-by":"publisher","award":["CE67_113_3000_042"],"award-info":[{"award-number":["CE67_113_3000_042"]}],"id":[{"id":"10.13039\/501100002873","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Graduate School and Faculty of Medicine, Chulalongkorn University","award":["HEA_FF_68_088_3000_014"],"award-info":[{"award-number":["HEA_FF_68_088_3000_014"]}]},{"name":"Graduate School and Faculty of Medicine, Chulalongkorn University","award":["CE67_113_3000_042"],"award-info":[{"award-number":["CE67_113_3000_042"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lumbar disc degeneration (LDD) is a common musculoskeletal disorder that leads to chronic pain and functional impairment. Recent studies have suggested that the vitamin D receptor (VDR) plays a key part in regulating matrix metabolism, inflammation, and apoptosis in intervertebral discs (IVDs). The objective of this study was to examine cytokine expression and DNA methylation status of the VDR gene in blood leukocytes and lumbar disc tissues from patients with varying degrees of LDD severity. We aimed to explore correlations between VDR expression, methylation status, and clinical parameters such as pain intensity and functional disability. We conducted a prospective case-control study including 50 participants 35 LDD patients and 15 lumbar disc herniation (LDH) controls. Blood and lumbar disc tissue samples were collected for RNA and DNA extraction, followed by quantitative real-time PCR for gene expression and methylation-specific polymerase chain reaction for VDR promoter methylation analysis. Serum and nucleus pulposus (NP) VDR protein levels were measured using enzyme-linked immunosorbent assay. Clinical parameters, including pain intensity (NRS) and functional disability (ODI), were assessed. LDD patients exhibited significantly lower VDR mRNA expression in both blood leukocytes and NP tissue compared to controls (p &lt; 0.05). LDD patients had significantly greater serum TNF-\u03b1 levels than controls (p &lt; 0.001); however, serum IL-1\u03b2 levels were not different between two groups. Serum VDR protein levels were elevated in LDD patients (p = 0.016), whereas NP VDR protein was significantly reduced in the LDD group (p = 0.013). VDR promoter methylation was significantly higher in both the blood and NP tissue of LDD patients compared to controls (p &lt; 0.001). Additionally, higher VDR promoter methylation in blood was correlated with advanced disc degeneration (p &lt; 0.05), while NP methylation was associated with all grades of degeneration (p &lt; 0.001). Serum VDR protein levels were inversely correlated with pain intensity (r = \u22120.39, p = 0.02), while NP VDR levels positively correlated with NRS scores (r = 0.43, p = 0.01). Aberrant VDR expression and increased promoter methylation are associated with LDD severity. Dysregulated VDR signaling, potentially mediated by DNA methylation, may play a critical role in the pathophysiology of LDD. These findings suggest that VDR could be a novel biomarker reflecting disease severity and a potential therapeutic target for managing LDD.<\/jats:p>","DOI":"10.3390\/ijms26073226","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:21:04Z","timestamp":1743398464000},"page":"3226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Downregulation and Hypermethylation of Vitamin D Receptor in Lumbar Disc Degeneration"],"prefix":"10.3390","volume":"26","author":[{"given":"Ladawan","family":"Vajarintarangoon","sequence":"first","affiliation":[{"name":"Center of Excellence in Osteoarthritis and Musculoskeleton, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Worawat","family":"Limthongkul","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biomechanics and Innovative Spine Surgery, Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7166-1381","authenticated-orcid":false,"given":"Weerasak","family":"Singhatanadgige","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biomechanics and Innovative Spine Surgery, Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9593-429X","authenticated-orcid":false,"given":"Vit","family":"Kotheeranurak","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biomechanics and Innovative Spine Surgery, Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8784-7604","authenticated-orcid":false,"given":"Wicharn","family":"Yingsakmongkol","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biomechanics and Innovative Spine Surgery, Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thananya","family":"Thongtan","sequence":"additional","affiliation":[{"name":"Center of Excellence in Osteoarthritis and Musculoskeleton, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinsuda","family":"Dechsupa","sequence":"additional","affiliation":[{"name":"Center of Excellence in Osteoarthritis and Musculoskeleton, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3852-9092","authenticated-orcid":false,"given":"Sittisak","family":"Honsawek","sequence":"additional","affiliation":[{"name":"Center of Excellence in Osteoarthritis and Musculoskeleton, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jitjumnong, M., Chalermkitpanit, P., Suantawee, T., Dechsupa, S., Vajarintarangoon, L., and Honsawek, S. (2022). Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231710125"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cazzanelli, P., and Wuertz-Kozak, K. (2020). MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103601"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1177\/2192568218770769","article-title":"Degenerative Lumbar Spine Disease: Estimating Global Incidence and Worldwide Volume","volume":"8","author":"Ravindra","year":"2018","journal-title":"Glob. Spine J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: Pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/10715762.2022.2094791","article-title":"VDR promotes nucleus pulposus cell mitophagy as a protective mechanism against oxidative stress injury","volume":"56","author":"Lan","year":"2022","journal-title":"Free Radic. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lan, T., Shen, Z., Hu, Z., and Yan, B. (2022). Vitamin D\/VDR in the pathogenesis of intervertebral disc degeneration: Does autophagy play a role?. Biomed. Pharmacother., 148.","DOI":"10.1016\/j.biopha.2022.112739"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jsbmb.2013.03.001","article-title":"Relationship between vitamin D receptor gene (VDR) polymorphisms, vitamin D status, osteoarthritis and intervertebral disc degeneration","volume":"138","author":"Colombini","year":"2013","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jsbmb.2019.03.013","article-title":"Age-dependent expression of the vitamin D receptor and the protective effect of vitamin D receptor activation on H2O2-induced apoptosis in rat intervertebral disc cells","volume":"190","author":"Tong","year":"2019","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101902","DOI":"10.1016\/j.arr.2023.101902","article-title":"Epigenetic modifications of inflammation in intervertebral disc degeneration","volume":"87","author":"Kang","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"662","DOI":"10.3897\/folmed.62.e50204.","article-title":"Vitamin D: A Review of its Effects on&nbsp;Epigenetics and Gene Regulation","volume":"62","author":"Snegarova","year":"2020","journal-title":"Folia Medica"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wimalawansa, S.J. (2019). Vitamin D Deficiency: Effects on Oxidative Stress, Epigenetics, Gene Regulation, and Aging. Biology, 8.","DOI":"10.3390\/biology8020030"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"379","DOI":"10.22603\/ssrr.2021-0187","article-title":"Influence of Age and Gender on Intervertebral Disk Degeneration and Height in the Thoracolumbar Spine","volume":"6","author":"Machino","year":"2022","journal-title":"Spine Surg. Relat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1002\/jor.23195","article-title":"Molecular mechanisms of biological aging in intervertebral discs","volume":"34","author":"Vo","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/sj.ijo.0802974","article-title":"Disc degeneration of the lumbar spine in relation to overweight","volume":"29","author":"Liuke","year":"2005","journal-title":"Int. J. Obes."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3233\/BMR-150516","article-title":"Association between intervertebral disc degeneration and the Oswestry Disability Index","volume":"30","author":"Middendorp","year":"2017","journal-title":"J. Back Musculoskelet. Rehabil."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4236\/ojmn.2017.72003","article-title":"Vitamin D Receptor Expression in Lumbar Disc Degeneration Patients","volume":"7","author":"Taha","year":"2017","journal-title":"Open J. Mod. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gasperini, B., Visconti, V.V., Ciccacci, C., Falvino, A., Gasbarra, E., Iundusi, R., Brandi, M.L., Botta, A., and Tarantino, U. (2023). Role of the Vitamin D Receptor (VDR) in the Pathogenesis of Osteoporosis: A Genetic, Epigenetic and Molecular Pilot Study. Genes, 14.","DOI":"10.3390\/genes14030542"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Habib, A.M., Nagi, K., Thillaiappan, N.B., Sukumaran, V., and Akhtar, S. (2020). Vitamin D and Its Potential Interplay With Pain Signaling Pathways. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00820"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yang, Q., Liu, Y., Guan, Y., Zhan, X., Xiao, Z., Jiang, H., and Wei, Q. (2019). Vitamin D Receptor gene polymorphisms and plasma levels are associated with lumbar disc degeneration. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-44373-2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3390\/ijms25010107","article-title":"Methylation of the Vitamin D Receptor Gene in Human Disorders","volume":"25","author":"Gasperini","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1534\/genetics.116.195594","article-title":"Trends in DNA Methylation with Age Replicate Across Diverse Human Populations","volume":"206","author":"Gopalan","year":"2017","journal-title":"Genetics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/08820139.2020.1810702","article-title":"Methylation Status of VDR Gene and its Association with Vitamin D Status and VDR Gene Expression in Pediatric Tuberculosis Disease","volume":"51","author":"Maruthai","year":"2022","journal-title":"Immunol. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104","DOI":"10.22203\/eCM.v030a08","article-title":"Disc in flames: Roles of TNF-\u03b1 and IL-1\u03b2 in intervertebral disc degeneration","volume":"30","author":"Johnson","year":"2015","journal-title":"Eur. Cell Mater."},{"key":"ref_24","first-page":"492","article-title":"Catabolic cytokine expressions in patients with degenerative disc disease","volume":"20","author":"Akyol","year":"2010","journal-title":"Turk Neurosurg."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, Y., Che, M., Xin, J., Zheng, Z., Li, J., and Zhang, S. (2020). The role of IL-1\u03b2 and TNF-\u03b1 in intervertebral disc degeneration. Biomed Pharmacother., 131.","DOI":"10.1016\/j.biopha.2020.110660"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mallio, C.A., Vadal\u00e0, G., Russo, F., Bernetti, C., Ambrosio, L., Zobel, B.B., Quattrocchi, C.C., Papalia, R., and Denaro, V. (2022). Novel Magnetic Resonance Imaging Tools for the Diagnosis of Degenerative Disc Disease: A Narrative Review. Diagnostics, 12.","DOI":"10.3390\/diagnostics12020420"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.1097\/00007632-200011150-00017","article-title":"The Oswestry Disability Index","volume":"25","author":"Fairbank","year":"2000","journal-title":"Spine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13046-015-0182-1","article-title":"Hypoxia-inducible MiR-182 promotes angiogenesis by targeting RASA1 in hepatocellular carcinoma","volume":"34","author":"Du","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/bioinformatics\/18.11.1427","article-title":"MethPrimer: Designing primers for methylation PCRs","volume":"18","author":"Li","year":"2002","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3226\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:06:11Z","timestamp":1760029571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,30]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073226"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073226","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,30]]}}}