Vajarintarangoon Ladawan, Limthongkul Worawat, Singhatanadgige Weerasak, Kotheeranurak Vit, Yingsakmongkol Wicharn, Thongtan Thananya, Dechsupa Sinsuda, Honsawek Sittisak
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.
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.
Int J Mol Sci. 2025 Mar 30;26(7):3226. doi: 10.3390/ijms26073226.
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 ( < 0.05). LDD patients had significantly greater serum TNF-α levels than controls ( < 0.001); however, serum IL-1β levels were not different between two groups. Serum VDR protein levels were elevated in LDD patients ( = 0.016), whereas NP VDR protein was significantly reduced in the LDD group ( = 0.013). VDR promoter methylation was significantly higher in both the blood and NP tissue of LDD patients compared to controls ( < 0.001). Additionally, higher VDR promoter methylation in blood was correlated with advanced disc degeneration ( < 0.05), while NP methylation was associated with all grades of degeneration ( < 0.001). Serum VDR protein levels were inversely correlated with pain intensity ( = -0.39, = 0.02), while NP VDR levels positively correlated with NRS scores ( = 0.43, = 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.
腰椎间盘退变（LDD）是一种常见的肌肉骨骼疾病，可导致慢性疼痛和功能障碍。最近的研究表明，维生素D受体（VDR）在调节椎间盘（IVD）的基质代谢、炎症和细胞凋亡中起关键作用。本研究的目的是检测不同LDD严重程度患者血液白细胞和腰椎间盘组织中VDR基因的细胞因子表达和DNA甲基化状态。我们旨在探讨VDR表达、甲基化状态与疼痛强度和功能障碍等临床参数之间的相关性。我们进行了一项前瞻性病例对照研究，包括50名参与者，35名LDD患者和15名腰椎间盘突出症（LDH）对照。采集血液和腰椎间盘组织样本用于RNA和DNA提取，随后进行定量实时PCR检测基因表达，以及甲基化特异性聚合酶链反应检测VDR启动子甲基化分析。使用酶联免疫吸附测定法测量血清和髓核（NP）VDR蛋白水平。评估临床参数，包括疼痛强度（NRS）和功能障碍（ODI）。与对照组相比，LDD患者血液白细胞和NP组织中的VDR mRNA表达均显著降低（<0.05）。LDD患者的血清TNF-α水平显著高于对照组（<0.001）；然而，两组之间的血清IL-1β水平没有差异。LDD患者的血清VDR蛋白水平升高（=0.016），而LDD组的NP VDR蛋白显著降低（=0.013）。与对照组相比，LDD患者血液和NP组织中的VDR启动子甲基化均显著更高（<0.001）。此外，血液中较高的VDR启动子甲基化与椎间盘退变进展相关（<0.05），而NP甲基化与所有退变等级相关（<0.001）。血清VDR蛋白水平与疼痛强度呈负相关（=-0.39，=0.02），而NP VDR水平与NRS评分呈正相关（=0.43，=0.01）。VDR表达异常和启动子甲基化增加与LDD严重程度相关。潜在由DNA甲基化介导的VDR信号失调可能在LDD的病理生理学中起关键作用。这些发现表明，VDR可能是反映疾病严重程度的新型生物标志物，也是治疗LDD的潜在靶点。
