NF-κB信号通路在雌激素牙周"骨保护效应"中的调控作用及机制研究

Although a number of studies suggested that estrogen deficiency may have an important role in chronic inflammatory periodontal diseases in post-menopausal women, the etiology of estrogen-associated periodontal diseases remains an enigma. Our previous study demonstrated that estrogen may provoke an imbalance in the remodeling sequence of periodontal tissues via modulating the inflammatory cytokines (TNF-α, IL-1β, IL-6, RANKL and OPG) expression in hPDL cells. However, exact signal transduction mechanisms of estrogen on inflammatory cytokines in periodontal ligament cells remain unclear. The NF-κB pathway is the most significant signaling target of a wide variety of inflammatory cytokines, which has been shown to have a central role in periodontal disease onset and progression. Furthermore, the modulation of this pathway on pro-inflammatory cytokines expression and alveolar bone resorption in periodontal tissue increases the possibility that may prove to be excellent targets for manipulating cytokines to resolve the periodontal disease in post-menopausal women. The present study was designed to explore whether NF-κB signaling pathway was involved in the bone-sparing effects of estrogen via modulating the inflammatory cytokines expression, suppressing osteoclastogenesis and bone resorption in periodontal tissue. Improved knowledge of signal transduction mechanisms and gene regulation involved in inflammatory responses, notably in pathway involving NF-κB, will certainly create new therapeutic targets useful in treating periodontal disease in post-menopausal women.

大量研究表明雌激素缺乏可能在绝经后女性慢性牙周疾病的发生、发展中具有重要意义。然而，雌激素影响牙周组织骨改建的确切分子机制目前尚不清楚。本课题组前期研究表明雌激素可以调控牙周膜细胞促炎因子TNF-α、IL-1β、IL-6及RANKL/OPG表达，影响牙周骨改建。目前雌激素影响牙周膜细胞促炎因子表达的信号转导机制尚不清楚。NF-κB信号途径在牙周组织促炎因子过表达及牙周疾病的发生、发展的重要作用引起了学者们的广泛关注。如何阻断信号转导途径以抑制雌激素缺乏诱导的牙周骨吸收是目前牙周炎治疗领域中较为关注的课题之一。本研究小组尝试以NF-κB信号转导通路为切入点，探讨NF-κB信号途径在雌激素对牙周膜细胞促炎因子IL-1β,TNF-α，IL-6及RANKL/OPG表达、破骨细胞分化以及骨吸收中的调控作用，深入了解雌激素牙周"骨保护效应"的可能机制，以期为绝经后女性慢性牙周炎的预防和治疗提供依据。

大量研究表明雌激素缺乏可能在绝经后女性慢性牙周疾病的发生、发展中具有重要意义。然而，雌激素影响牙周组织骨改建的确切分子机制目前尚不清楚。本课题组前期研究表明雌激素可以调控牙周膜细胞促炎因子TNF-α、IL-1β、IL-6及RANKL/OPG表达，影响牙周骨改建。目前雌激素影响牙周膜细胞促炎因子表达的信号转导机制尚不清楚。NF-κB信号途径在牙周组织促炎因子过表达及牙周疾病的发生、发展的重要作用引起了学者们的广泛关注。如何阻断信号转导途径以抑制雌激素缺乏诱导的牙周骨吸收是目前牙周炎治疗领域中较为关注的课题之一。本研究小组尝试以NF-κB信号转导通路为切入点，探讨NF-κB信号途径在雌激素对牙周膜细胞促炎因子IL-1β,TNF-α，IL-6及RANKL/OPG表达、破骨细胞分化以及骨吸收中的调控作用，深入了解雌激素牙周“骨保护效应”的可能机制，以期为绝经后女性慢性牙周炎的预防和治疗提供依据。本研究表明：（1）NF-κB 信号系统参与了雌激素对LPS诱导的牙周膜细胞促炎因子表 达的调控。即LPS可激活NF-κB 信号通路，而E2对LPS诱导的牙周膜细胞IκBα蛋白降解 ，IκBα磷酸化及NF-κB p65核内转录具有显著的抑制作用；（2）NF-κB 信号系统参与了LPS对破骨样细胞分化形成的诱导。即LPS可 激活NF-κB信号通路，诱导OLC形成并促进骨吸收，而NF-κB抑制剂PDTC对LPS诱导的OLC 形成及骨吸收具有显著的抑制作用。