Mechanism of Bone Resorption in Periodontitis

点击翻译按钮获取中文摘要

 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.