Mechanism of bone resorption in periodontitis

 描述（由申请人提供）：牙周炎是一种口腔炎性疾病，由于牙槽骨吸收导致牙龈肿胀和牙齿脱落，降低生活质量。超过47%的美国成年人患有牙周炎。牙周炎也会增加患心血管疾病和风湿性关节炎的风险。研究表明，对口腔细菌的病理性免疫反应是牙周炎和随后的破骨细胞活化的主要原因，导致牙槽骨丢失。然而，牙周炎诱导骨吸收的机制还不完全清楚。因此，本提案的目的是确定和表征在这种不良条件下负责骨吸收的分子和细胞机制。我们发现的基因突变负责一种罕见的颅面疾病“巨像症”可能提供新的见解的机制。巨颌症是一种遗传性疾病，其特征是由于含有大量破骨细胞的炎性病变增殖而导致下颌骨和上颌骨过度破坏。我们以前发现，信号衔接蛋白SH 3结构域结合蛋白2（SH 3BP 2）中的功能获得性突变是导致这种罕见疾病的原因。巨结肠小鼠模型显示，该突变增加了对细菌病原体的反应性，并增强了巨噬细胞产生的肿瘤坏死因子（TNF）-α。与突变型SH 3BP 2相互作用的SYK激酶对Toll样受体2和4的过度激活是炎症的主要引发剂。此外，我们还发现SH 3BP 2功能的获得和丧失分别增加或减少了破骨细胞对TNF-α的反应。最近，这些研究已经采取了一个令人兴奋的新方向的基础上，我们的新发现，SH 3BP 2获得和功能丧失突变有一个深远的影响，对骨质流失的易感性在小鼠模型的牙周炎。这提升了SH 3BP 2的重要性，超出了其在罕见遗传性疾病中的作用，并表明SH 3BP 2在牙周炎的炎症和骨吸收中起关键作用。因此，我们的数据使我们提出了一个新的假设，即SH 3BP 2负责调节牙周炎进展过程中的破骨细胞活性，导致牙槽骨丢失。为了验证这一假设，提出了三个具体目标：目标1）确定SH 3BP 2功能获得增加牙周炎骨丢失的机制。目的2）确定SH 3BP 2功能丧失保护牙周炎中骨丢失的机制。目的3）研究SYK抑制剂对牙周炎骨吸收的影响。完成所提出的具体目标将进一步阐明SH 3BP 2作为牙周炎中炎性骨丢失的关键信号传导介质的作用，并将确定其对破骨细胞生成重要的下游炎症介质。证实SH 3BP 2功能丧失或抑制其下游介质SYK可以防止牙周炎相关的骨丢失，将为治疗牙周炎开辟新的机会，靶向这些途径。

 DESCRIPTION (provided by applicant): Periodontitis is an oral inflammatory disease resulting in swollen gingiva and tooth loss due to resorption of alveolar bones, which reduce the quality of life. Over 47% of adult U.S. population has periodontitis. Periodontitis can also increase risk for cardiovascular disease and rheumatoid arthritis. Studies have suggested that a pathologic immune response to oral bacteria is primarily responsible for periodontitis and subsequent activation of osteoclasts, resulting in alveolar bone loss. However, the mechanisms of the induction of bone resorption in periodontitis are not fully understood. Therefore, the goal of this proposal is to identify and characterize the molecular and cellular mechanisms responsible for bone resorption in this poor condition. Our discovery of the gene mutations responsible for a rare craniofacial disorder "Cherubism" may provide novel insights into the mechanisms. Cherubism is a genetic disorder characterized by excessive destruction of mandibular and maxillary bones due to proliferation of inflammatory lesions containing a large number of osteoclasts. We have previously discovered that gain-of-function mutations in the signaling adaptor protein SH3-domain binding protein 2 (SH3BP2) are responsible for this rare condition. The mouse model of cherubism showed that the mutation increases responsiveness to bacterial pathogens and enhances tumor necrosis factor (TNF)-α production by macrophages. Hyper-activation of the toll-like receptor 2 and 4 by SYK kinase that interacts with mutant SH3BP2 is a major initiator of inflammation. Furthermore, we have discovered that gain- and loss-of-function of SH3BP2 respectively increases or decreases osteoclast formation in response to TNF-α. Recently, these studies have taken an exciting new direction based on our new discovery that SH3BP2 gain- and loss-of-function mutations have a profound effect on susceptibility to bone loss in a mouse model of periodontitis. This elevates the significance of SH3BP2 beyond its role in a rare inherited disorder and suggests that SH3BP2 is a critical player in inflammation and bone resorption in periodontitis. Therefore, our data have led us to a new hypothesis that SH3BP2 is responsible for the regulation of osteoclast activity during the progression of periodontitis resulting in alveolar bone loss. To test the hypothesis, the three specific aims are proposed: Aim 1) Determine the mechanism by which SH3BP2 gain-of-function increases bone loss in periodontitis. Aim 2) Determine the mechanism by which SH3BP2 loss- of-function protects against bone loss in periodontitis. Aim 3) Determine the effect of SYK inhibition on bone resorption in periodontitis. Completion of the proposed specific aims will further delineate the role of SH3BP2 as a key signaling mediator of inflammatory bone loss in periodontitis and will identify its downstream inflammatory mediators important for osteoclastogenesis. Confirmation that loss-of-function of SH3BP2 or inhibition of its downstream mediator SYK can protect against periodontitis-associated bone loss will open up new opportunities for targeting these pathways therapeutically for the treatment of periodontitis.