Downregulation and Hypermethylation of Vitamin D Receptor in Lumbar Disc Degeneration

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 (<i>p</i> < 0.05). LDD patients had significantly greater serum TNF-α levels than controls (<i>p</i> < 0.001); however, serum IL-1β levels were not different between two groups. Serum VDR protein levels were elevated in LDD patients (<i>p</i> = 0.016), whereas NP VDR protein was significantly reduced in the LDD group (<i>p</i> = 0.013). VDR promoter methylation was significantly higher in both the blood and NP tissue of LDD patients compared to controls (<i>p</i> < 0.001). Additionally, higher VDR promoter methylation in blood was correlated with advanced disc degeneration (<i>p</i> < 0.05), while NP methylation was associated with all grades of degeneration (<i>p</i> < 0.001). Serum VDR protein levels were inversely correlated with pain intensity (<i>r</i> = -0.39, <i>p</i> = 0.02), while NP VDR levels positively correlated with NRS scores (<i>r</i> = 0.43, <i>p</i> = 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.