Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss

Abstract

Background and Objective Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH)2D3, induces the expression of the antimicrobial peptide LL‐37 and innate immune mediators in cultured human gingival epithelial cells (GECs). The aim of this study was to further delineate the mechanism by which vitamin D enhances the innate defense against the development of periodontal disease (PD). Materials and Methods Wild‐type C57Bl/6 mice were made deficient in vitamin D by dietary restriction. Cultured primary and immortalized GEC were stimulated with 1,25(OH)2D3, followed by infection with Porphyromonas gingivalis, and viable intracellular bacteria were quantified. Conversion of vitamin D3 to 25(OH)D3 and 1,25(OH)2D3 was quantified by ELISA. Effect of vitamin D on basal IL‐1α expression in mice was determined by topical administration to the gingiva of wild‐type mice, followed by qRT‐PCR. Results Dietary restriction of vitamin D led to alveolar bone loss and increased inflammation in the gingiva in the mouse model. In primary human GEC and established human cell lines, treatment of GEC with 1,25(OH)2D3 inhibited the intracellular growth of P. gingivalis. Cultured GEC expressed two 25‐hydroxylases (CYP27A1 and CYP2R1), as well as 1‐α hydroxylase, enabling conversion of vitamin D to both 25(OH)D3 and 1,25(OH)2D3. Topical application of both vitamin D3 and 1,25(OH)2D3 to the gingiva of mice led to rapid inhibition of IL‐1α expression, a prominent pro‐inflammatory cytokine associated with inflammation, which also exhibited more than a 2‐fold decrease from basal levels in OKF6/TERT1 cells upon 1,25(OH)2D3 treatment, as determined by RNA‐seq. Conclusion Vitamin D deficiency in mice contributes to PD, recapitulating the association seen in humans, and provides a unique model to study the development of PD. Vitamin D increases the activity of GEC against the invasion of periodontal pathogens and inhibits the inflammatory response, both in vitro and in vivo. GEC can convert inactive vitamin D to the active form in situ, supporting the hypothesis that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.

Expression of vitamin D 1α-hydroxylase in human gingival fibroblasts in vivo

“…Although we focused on hGFs, epithelial tissues were also observed in the present study, and gingival epithelia were found to be CYP27B1 positive in both groups, which was in line with the findings of other researchers (McMahon et al, 2011;Menzel et al, 2019). What should be pointed out is that the distribution of CYP27B1 expression differed between the two groups (Fig.…”

Current Knowledge Regarding the Interaction Between Oral Bone Metabolic Disorders and Diabetes Mellitus

“…Some studies have concluded that taking vitamin D may prevent the progression of periodontal disease ( 113 ). Menzel et al ( 114 ) have analyzed the relationship between vitamin D in the gingival epithelium and loss of alveolar bone, and suggested that dietary restriction of vitamin D leads to alveolar bone loss and increased inflammation in the gingiva. Boggess et al ( 115 ) have found that vitamin D and calcium supplementation increase jaw BMD and inhibit alveolar bone loss, and Garcia et al ( 116 ) have reported that supplementation with 800–1,000 IU vitamin D per day reduces the severity of periodontal disease.…”

Microbial and Host Factors That Affect Bacterial Invasion of the Gingiva

“…Epithelial VDR signaling protects the integrity of the intestinal barrier by several mechanisms, including upregulation of junctional protein expression, stabilization of TJ structures, upregulation of cathelicidin (the precursor of LL-37) and β-defensins, and inhibition of inflammation-induced epithelial cell apoptosis (Sun 2010). Menzel et al (2019) reported that treatment of oral epithelial cells with 1,25(OH) 2 D 3 , the active form of vitamin D, upregulated LL-37 expression but downregulated inflammatory cytokine IL-1α. Interestingly, treatment of oral epithelial cells with 1,25(OH) 2 D 3 also reduced invasion by P. gingivalis , the mechanisms for which await further elucidation.…”