Over 47% of American adults aged 30 and over have periodontitis. Further, periodontitis is twice as prevalent in diabetics as in non-diabetics, and type 2 diabetes (T2D) currently afflicts 40 million Americans. T2D-associated periodontitis is severe and, in many cases, refractory to current treatments due to the altered and aberrant functions of bone cells in hyperglycemic conditions. Therefore, developing an effective method to restore and regenerate lost alveolar bone to reserve the natural teeth in diabetics is critically important. Adiponectin, an adipokine, has anti-inflammatory and anti-diabetic properties. We have found that adiponectin inhibits differentiation and activity of osteoclasts and significantly decreases alveolar bone loss. At the same time, it promotes the osteoblast niche and mesenchymal stem cell migration, and enhances bone defect healing. However, adiponectin protein-based therapy has disadvantages that limit its clinical application, including adverse immunoreactions and the need for constant IV injection of high doses for therapeutic effect. An adiponectin receptor agonist, AdipoRon (APR) was recently identified (Nature 503:493-9, 2013), which can be orally administrated to ameliorate insulin resistance and glucose intolerance, and prolong the shortened lifespan of diabetic mice. Our preliminary studies indicate that APR upregulates expression and activity of adiponectin receptors exerting favorable effects on bone cell metabolism. Our purpose is to use APR, a small molecule chemical compound, as a novel therapeutic agent to effectively treat diabetic periodontitis. Our central hypothesis is that, in addition to systemically controlling hyperglycemia and inflammation, APR directly triggers molecular signals that correct the imbalance of bone resorption and formation, reversing pathology and promoting regeneration of lost alveolar bone, and allowing the natural teeth to be reserved.
In Aim 1 we will first determine the affinity and efficacy of APR binding to adiponectin receptors in bone cells, initiation of downstream signal mediator expression, and enhancement of bone formation. To verify the specificity and affinity of the interaction between this novel exogenous agonist and endogenous receptor, we will use receptor knock out mice.
In Aim 2 we will delineate the APR effect in ameliorating and correcting diabetic 'mobilopathy' - in which cell differentiation, recruitment and migration are seriously impaired in diabetes. We will use an adiponectin knock out mouse line to determine if APR can effectively surrogate adiponectin in promoting the necessary microenvironment and deploying sufficient bone forming cells to regenerate alveolar bone damaged in periodontitis.
In Aim 3 we will generate experimental periodontitis in a mouse model of diabetes to further determine the overall effects of APR in reducing hyperglycemia and inflammation as well as its anabolic effect for periodontal bone regeneration. This translational research will yield initial characterization of a novel therapeutic agent with strong potential for treating diabetic periodontal disease and provide baseline information for drug development for treating periodontitis and other bone diseases associated with diabetes.

Public Health Relevance

Periodontitis in diabetics is more common and refractory than in non-diabetics. AdipoRon (APR) is a newly discovered chemical compound and has multilayer of functions including reducing blood sugar level and general inflammation, inhibiting bone resorption and promoting bone formation and regeneration. This translational research aims to use APR as a novel and potent agent to develop a viable therapy for treating periodontitis and other bone diseases in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE026507-02
Application #
9398118
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Wan, Jason
Project Start
2016-12-12
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Tufts University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Zhang, Lan; Tang, Yin; Zhu, Xiaofang et al. (2017) Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice. J Bone Miner Res 32:2466-2475
Xuan, Dongying; Han, Qianqian; Tu, Qisheng et al. (2016) Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages. J Cell Physiol 231:1090-6