Vitamin D’s Effect on the Proliferation and Inflammation of Human Intervertebral Disc Cells in Relation to the Functional Vitamin D Receptor Gene FokI Polymorphism

Abstract

Vitamin D is known to have immunomodulatory effects, is involved in osteo-cartilaginous metabolism, and may have a role in human intervertebral disc pathophysiology. Although a link between vitamin D receptor (VDR) gene variants and disc degeneration-related pathologies has been observed, its functional contribution to pathologic processes has not been assessed yet. The aim of this study was to investigate the response of disc cells to vitamin D in terms of the regulation of proliferation, metabolism, and inflammatory processes, with a particular focus on the FokI VDR genotype. However, although it was found that vitamin D had a pro-apoptotic effect regardless of genotype, an up-regulation of IL-1Ra and downregulation of IL-6 was found to be evident only in Ff cells. Regarding the metabolic effects, in Ff cells, vitamin D promoted an upregulation of the aggrecan in inflammatory conditions but did not have an effect on the expression of collagen-related markers. Moreover, cells bearing the Ff genotype were the most responsive to vitamin D in the upregulation of catabolic markers. In addition, in contrast to the FF genotype, vitamin D downregulated the vitamin D-dependent signaling pathway in inflamed Ff cells, counteracting the inflammation-mediated catabolic effects. In conclusion, Ff cells were found to be more responsive to the anti-inflammatory and catabolic effects of vitamin D, which is likely to be related to matrix remodeling.

High-Throughput Gene and Protein Analysis Revealed the Response of Disc Cells to Vitamin D, Depending on the VDR FokI Variants

“…Overall, it was observed a modulation of common pathways, particularly involved in matrix remodeling and chondrocytes hypertrophy and often regulated in an opposite way depending on the FokI VDR genotype. In presence of an inflammatory stimulus, vitamin D action on disc cells appeared less evident, in particular in FF cells, confirming that Ff cells are more responsive to the hormone, as previously observed [24].…”

“…In a recent preliminary study on a selected, small panel of markers [24], the regulation of proliferation, metabolism, and inflammatory processes after vitamin D treatment in disc cells was analyzed, with particular attention to the role of FokI VDR polymorphism. Vitamin D showed an inhibitory effect on the proliferation and metabolic activity of the disc cells and a pro-apoptotic induction, regardless to the VDR genotype, while Ff bearing cells showed the most anti-inflammatory and catabolic behavior.…”

Vitamin D and Human Health

“…The study was contacted on intervertebral disc cells derived from patients with discopathy or spondylolisthesis. Interestingly, it seems that the Ff variant of Fok I genotype of the VDR gene is more responsive to the anti-inflammatory effects of vitamin D and could be used as a diagnostic factor in discopathies [6]. Furthermore, the effects of the VDR SNPs were also investigated in acute pancreatitis (AP).…”

Advanced Strategies for the Regeneration of Lumbar Disc Annulus Fibrosus

“…A decrease in the AF cell density, as frequently observed in degenerated IVDs, alters the balance of anabolism:catabolism ratio in the extracellular matrix (ECM), changing the AF mechanical, biological, and structural properties [ 69 , 70 , 71 ]. Therefore, regenerative strategies aim to repopulate a degenerated IVD with healthy cells (cell therapy) or stimulating the existing cells to regulate the ECM reaching an enhanced composition, quantity, and structure (biomolecule and gene therapy) [ 81 , 82 , 83 , 84 , 85 ]. ECM remodeling is crucial to control the action of biochemical mediators such as cytokines (interleukins), growth factors, and enzymes (metalloproteinases and heparanase) to ultimately stop or reverse the IVD degeneration process [ 86 , 87 , 88 , 89 ].…”