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)-? 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-?. 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.

Public Health Relevance

The goal of this project is to identify the novel molecular mechanisms responsible for the bone loss in periodontal diseases. Successful delineation of the mechanisms will facilitate the design of more effective and safer drugs for the treatment of patients suffering from tooth loss associated with periodontitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE025870-01
Application #
9081087
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Wan, Jason
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110