Topical Vitamin D and Periodontal Disease

项目总结/摘要 牙周病与牙龈卟啉单胞菌的增加有关， 龈下缝隙中的微生物群和慢性炎症导致骨吸收，最终导致牙齿 损失维生素D是最有名的一个主要因素，维持钙稳态，是所需的骨 发育和体内平衡。然而，越来越清楚的是，维生素D在免疫方面具有深远的作用。 还有炎症牙周病的危害有哪些？ 维生素D缺乏症的患者我们最近公布的数据显示， 维生素D，1，25（OH）2D 3，通过牙龈上皮细胞（GEC）促进抗牙龈卟啉单胞菌的抗菌活性， 并抑制促炎细胞因子表达。小鼠实验性维生素D缺乏导致牙龈炎 炎症和骨质流失。然而，研究口服维生素D补充剂对 牙周病导致了相互矛盾的结果，可能是由于自然反馈机制。因此我们 假设局部给予牙龈维生素D可以避免这个问题。我们 初步结果表明，当非活性维生素D直接输送到牙龈表面时， 上皮细胞，在体外和小鼠中，我们观察到维生素D介导的基因的快速诱导，以及 抑制促炎细胞因子，无细胞毒性。我们还观察到上皮细胞 非活性维生素D3通过上皮细胞转化为非活性中间体（25 OHD 3）和活性1，25（OH）2D 3。 表达的羟化酶，并且这种转化导致宿主防御肽的产量增加， LL-37因此，我们的总体假设是，牙龈上皮细胞保持其自身的内在调节 维生素D状态，并且局部递送维生素D至口腔上皮允许直接引入高维生素D水平。 活性维生素D的浓度到组织。这种传递可以导致维生素D调节基因的调节 它可以下调炎症，防止周围病原菌的生长， 损失为了解决这一问题，我们提出了以下具体目标：1）量化维生素D之间的关系 和牙周病的实验。2)定义口腔微生物组的变化， 维生素D. 3)描述维生素D介导的诱导培养的先天免疫的机制， 人GEC。总之，这些目标将支持我们的假设，即维生素D对牙周健康至关重要， 将有助于定义这种情况发生的机制，并将提供一个原则证明， 在口腔中施用维生素D可以维持这种健康状态。维生素D的作用很复杂， 多方面的，但利用其有益的活动有可能改变牙周实践取代 昂贵的机械和外科手术，合理、安全和可靠的局部治疗， 毒性

PROJECT SUMMARY/ABSTRACT Periodontal disease is associated with an increase in Porphyromonas gingivalis, dysbiosis of the commensal microbiota in the subgingival crevice, and chronic inflammation resulting in bone resorption, and ultimately tooth loss. Vitamin D is best known as a principal factor that maintains calcium homeostasis and is required for bone development and homeostasis. However, it is becoming clear that vitamin D has profound actions in immunity and inflammation as well. Both the chronic and aggressive forms of periodontal disease have been associated with vitamin D deficiency in numerous populations. Our recently published data show that the active form of vitamin D, 1,25(OH)2D3, promotes anti-bacterial activity against P. gingivalis by gingival epithelial cells (GEC), and inhibits pro-inflammatory cytokine expression. Experimental vitamin D deficiency in mice leads to gingival inflammation and bone loss. However, clinical trials examining the effect of oral vitamin D supplementation on periodontal disease have led to conflicting results, likely due to natural feedback mechanisms. We therefore hypothesized that topical administration of vitamin D to the gingiva could circumvent this problem. Our preliminary results indicate that when inactive vitamin D is delivered directly to the surface of the gingival epithelium, both in vitro and in mice, we observe a rapid induction of vitamin D-mediated genes, as well as an inhibition of pro-inflammatory cytokines, without cytotoxicity. We also observed that the epithelial cells convert inactive vitamin D3 to both the inactive intermediate (25OHD3), and to active 1,25(OH)2D3 through epithelial cell- expressed hydroxylases, and that this conversion resulted in increased production of the host defense peptide, LL-37. Thus, our overarching hypothesis is that that the gingival epithelium maintains its own intrinsic regulation of vitamin D status, and that topical delivery of vitamin D to the oral epithelium allows direct introduction of high concentrations of active vitamin D to the tissue. This delivery can lead to regulation of vitamin D-regulated genes that can downregulate inflammation and prevent the growth of periopathogenic bacteria, and the resulting bone loss. To address this, we propose the following specific aims: 1) Quantify the relationship between vitamin D and periodontal disease in a mouse model. 2) Define the shifts in the oral microbiome regulated by vitamin D. 3) Characterize the mechanism of vitamin D-mediated induction of innate immunity in cultured human GEC. Together, these aims will support our hypothesis that vitamin D is essential for periodontal health, will help define the mechanism by which this occurs, and will provide a proof of principle that topical administration of vitamin D in the oral cavity can maintain this health status. Vitamin D’s actions are complex and multifaceted, but harnessing its beneficial activities has the potential to change periodontal practice replacing expensive mechanical and surgical procedures with well-reasoned, safe and reliable topical treatments with no toxicity.