Immune Cytokines Promote Oral Bone Loss Through IKK

免疫细胞因子通过 IKK 促进口腔骨质流失

• 批准号: 7556738
• 负责人: CUN-YU WANG
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556738
• 关键词: Affect; Alveolar Bone Loss; Attenuated; Bacterial Infections; Bone Diseases; Bone Formation Inhibition; Bone Matrix; Bone Resorption; Cells; Condition; Coupled; Dental; Deposition; Disease; Dominant-Negative Mutation; Ensure; Environment; Equilibrium; Extracellular Matrix; Gene Expression; Host Defense; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-17; Lymphocyte; Mediating; Mediator of activation protein; Molecular; Molecular Genetics; Mus; NF-kappa B; Oral; Oral cavity; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; Periapical Diseases; Phosphotransferases; Physiological; Play; Proteins; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Small Interfering RNA; Staging; Staining method; Stains; Testing; Time; Tooth Diseases; Tooth Loss; Transgenic Mice; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Western Blotting; activating transcription factor; alizarin; alveolar bone; base; bone; bone loss; cytokine; extracellular; fight against; human TNF protein; in vivo; insight; kinase inhibitor; knock-down; macrophage; mineralization; periapical; prevent; promoter; response; soft tissue; tomography

DESCRIPTION (provided by applicant): Oral alveolar bone loss is commonly caused by periodontal and periapical diseases associated with bacterial infection. At the initial stage of host defense, immune cells produce a variety of immune cytokines to fight against the bacterial infection. Under physiological condition, bone resorption is delicately balanced and coupled with bone extracellular matrix deposition or bone formation, ensuring that new bone is generated where old bone is removed. However, the persistent immune response in periodontal and periapical diseases disrupts the balance between bone formation and bone resorption, resulting in alveolar bone destruction and tooth loss. Currently while there is a good understanding of how immune cells and the cytokines they secret stimulate oral bone resorption, the underlying mechanism by which oral bone formation is inhibited in oral osteoimmune responses remains a mystery. Our preliminary studies revealed that immune cytokines activate I:B kinase (IKK) to inhibit osteoblast differentiation. Using two lines of transgenic mice which specifically expressed the IKK inhibitors in osteoblasts, we discovered that IKK activation by immune cytokines potently impaired bone forming function of differentiated/mature osteoblasts in osteoporotic immune bone loss. Based on these exciting findings, we hypothesize that the activation of IKK by immune cytokines in osteoblasts mediates the uncoupling of bone formation from bone resorption in oral immune bone loss. To fully understand the molecular mechanisms of alveolar bone loss due to infection, we propose the following four specific aims. Specific Aim 1 is to examine whether immune cytokines inhibit oral osteogenesis by activating IKK in vitro. Specific Aim 2 is to determine whether IKK activation plays a critical role in oral inflammatory bone loss in vivo by inhibiting bone formation. Specific Aim 3 is to determine whether the inhibition of IKK activation attenuates oral bone loss by maintaining osteoblast function under an osteoporotic condition in vivo. Specific Aim 4 is to explore the molecular mechanisms by which immune cytokines mediate the uncoupling of bone formation from bone resorption through IKK in osteoimmune responses. In summary, these studies will provide new insights into the osteoimmune mechanisms of oral bone loss, and may have important implications in the treatment of oral and systemic bone disorders. Project Narrative: Gum disease and dental pulpal infection often cause soft tissue and oral alveolar bone destruction, resulting in tooth loss. At the initial stage of host defense, immune cells such as lymphocytes and macrophages produce a variety of inflammatory mediators to fight against bacterial infection. Due to the open environment of the oral cavity, oral immune responses are not easily resolved and frequently cause alveolar bone loss. It has been known for a long time that inflammatory mediators not only stimulate oral bone resorption, but also inhibit oral bone formation. While there is a good understanding of how oral bone resorption is triggered, the underlying mechanisms by which oral bone formation is suppressed remain a mystery in oral inflammation. Our preliminary studies suggest that the activation of I:B kinase (IKK) by inflammatory mediators may play a critical role in the inhibition of oral bone formation. To fully understand the molecular mechanisms of alveolar bone loss due to infection, we will examine whether the inhibition of IKK abolishes inflammatory mediator-mediated inhibition of oral osteogenesis. We will determine whether the inhibition of IKK prevents oral bone loss induced by the dental pulpal infection by maintaining osteoblast functions. Finally, we will explore how IKK suppresses oral bone formation by inducing gene expression. In summary, these studies will provide new insights into the molecular mechanisms of oral bone loss due to infection, and may have important implications in the treatment of oral and systemic bone disorders.

描述（由申请人提供）：口腔牙槽骨丢失通常由与细菌感染相关的牙周和根尖周疾病引起。在宿主防御的初始阶段，免疫细胞产生多种免疫细胞因子来对抗细菌感染。在生理条件下，骨吸收是微妙的平衡，并与骨细胞外基质沉积或骨形成相结合，确保在旧骨被去除的地方产生新骨。然而，牙周和尖周疾病中持续的免疫反应破坏了骨形成和骨吸收之间的平衡，导致牙槽骨破坏和牙齿脱落。目前，虽然对免疫细胞及其分泌的细胞因子如何刺激口腔骨吸收有了很好的了解，但口腔骨形成在口腔骨免疫反应中受到抑制的潜在机制仍然是一个谜。我们的初步研究表明，免疫细胞因子激活I：B激酶（IKK）抑制成骨细胞分化。使用两种转基因小鼠，特别是在成骨细胞表达IKK抑制剂，我们发现，IKK激活免疫细胞因子的分化/成熟的成骨细胞在骨质疏松性免疫性骨丢失的骨形成功能的有力损害。基于这些令人兴奋的发现，我们假设成骨细胞中免疫细胞因子激活IKK介导了口腔免疫性骨丢失中骨形成与骨吸收的解偶联。为了充分了解感染引起牙槽骨丢失的分子机制，我们提出了以下四个具体目标。具体目的1是检查免疫细胞因子是否通过体外激活IKK来抑制口腔成骨。具体目标2是确定IKK激活是否通过抑制骨形成在体内口腔炎性骨丢失中起关键作用。具体目标3是确定在体内骨质疏松条件下，抑制IKK活化是否通过维持成骨细胞功能来减轻口腔骨丢失。具体目的4是探讨免疫细胞因子介导骨形成与骨吸收通过IKK在骨免疫反应中解偶联的分子机制。总之，这些研究将为口腔骨丢失的骨免疫机制提供新的见解，并可能对口腔和全身性骨疾病的治疗具有重要意义。项目叙述：牙龈疾病和牙髓感染常引起软组织和口腔牙槽骨破坏，导致牙齿脱落。在宿主防御的初始阶段，免疫细胞如淋巴细胞和巨噬细胞产生多种炎症介质来对抗细菌感染。由于口腔的开放环境，口腔免疫反应不容易解决，经常导致牙槽骨丢失。炎症介质不仅刺激口腔骨吸收，而且抑制口腔骨形成。虽然对口腔骨吸收是如何触发的有了很好的理解，但口腔骨形成受到抑制的潜在机制在口腔炎症中仍然是一个谜。我们的初步研究表明，炎症介质激活I：B激酶（IKK）可能在抑制口腔骨形成中起关键作用。为了充分了解感染引起牙槽骨丢失的分子机制，我们将研究抑制IKK是否能消除炎症介质介导的口腔成骨抑制。我们将确定抑制IKK是否通过维持成骨细胞功能来防止牙髓感染引起的口腔骨丢失。最后，我们将探讨IKK如何通过诱导基因表达抑制口腔骨形成。总之，这些研究将提供新的见解口腔骨丢失的分子机制，由于感染，并可能在口腔和全身性骨疾病的治疗具有重要意义。