Immune Cytokines Promote Oral Bone Loss Through IKK

描述（由申请人提供）：口腔牙槽骨丢失通常是由与细菌感染相关的牙周和根尖周疾病引起的。在宿主防御的初始阶段，免疫细胞产生多种免疫细胞因子对抗细菌感染。在生理状态下，骨吸收是微妙平衡的，并与骨细胞外基质沉积或骨形成相结合，确保旧骨被移除的地方产生新骨。然而，牙周和根尖周围疾病的持续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已经有了很好的了解，但在口腔骨免疫反应中，抑制口腔骨形成的潜在机制仍然是一个谜。我们的初步研究发现免疫细胞因子激活I:B激酶（IKK）抑制成骨细胞分化。利用两种在成骨细胞中特异性表达IKK抑制剂的转基因小鼠，我们发现IKK被免疫细胞因子激活后，在骨质疏松性免疫骨质流失中，分化/成熟成骨细胞的骨形成功能会受到严重损害。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对IKK的激活介导了口腔免疫性骨质流失中骨吸收和骨形成的分离。为了充分了解感染引起的牙槽骨丢失的分子机制，我们提出以下四个具体目标。特异性目的1是研究免疫细胞因子是否通过体外激活IKK抑制口腔成骨。特异性目的2是确定IKK激活是否通过抑制骨形成在体内口腔炎症性骨丢失中起关键作用。具体目的3是确定在体内骨质疏松状态下，IKK激活的抑制是否通过维持成骨细胞功能来减轻口腔骨质流失。特异性目的4是探索免疫细胞因子通过IKK介导骨免疫应答中骨吸收与骨形成解偶联的分子机制。总之，这些研究将为口腔骨质流失的骨免疫机制提供新的见解，并可能对口腔和全身骨骼疾病的治疗具有重要意义。项目描述：齿龈疾病和牙髓感染常造成口腔软组织和牙槽骨破坏，导致牙齿脱落。在宿主防御的初始阶段，淋巴细胞、巨噬细胞等免疫细胞产生多种炎症介质对抗细菌感染。由于口腔的开放环境，口腔免疫反应不易解决，经常造成牙槽骨丢失。很早以前人们就知道，炎症介质不仅能刺激口腔骨吸收，还能抑制口腔骨形成。虽然对口腔骨吸收是如何被触发已经有了很好的了解，但在口腔炎症中，抑制口腔骨形成的潜在机制仍然是一个谜。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的牙槽骨丢失的分子机制，我们将研究IKK的抑制是否会消除炎症介质介导的口腔成骨抑制。我们将确定IKK的抑制是否通过维持成骨细胞的功能来防止牙髓感染引起的口腔骨质流失。最后，我们将探讨IKK如何通过诱导基因表达来抑制口腔骨形成。综上所述，这些研究将为了解感染导致的口腔骨质流失的分子机制提供新的见解，并可能对口腔和全身骨骼疾病的治疗具有重要意义。

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.