Periodontitis is twice as prevalent in diabetics as in non-diabetics. Diabetic periodontal diseases are more severe and refractory because T2DM and obesity trigger the release of excess inflammatory factors, such as TNF-1 and IL-6, which in turn stimulate osteoclasts to resorb the alveolar bone that supports the teeth. Adiponectin, a fat cell derived hormone, is emerging as a potent molecule with multiple biological functions including regulating insulin sensitivity, suppressing inflammation, and improving diabetic symptoms. It also promotes osteoblastic differentiation and bone formation. Our recent studies have shown that adiponectin inhibits osteoclast differentiation and increases osteoclast apoptosis. Our long-term objective is to identify and characterize an ideal endogenous mediator as a potent therapeutic remedy for the treatment of the widely prevalent T2DM-associated periodontitis. The objective of this application is to investigate the mechanisms of adiponectin in the pathogenesis of T2DM-associated periodontitis and to specifically reconstruct the inflammatorily damaged periodontal tissues by the replenishment of adiponectin in vivo. The central hypothesis to be tested is that the decreased level of adiponectin, together with the consequent removal of its suppressive effects on osteoclasts and proinflammatory factors, contributes to the pathogenesis of T2DM and T2DM-associated periodontitis. Also, a systemic adiponectin infusion promotes the reconstruction of the damaged periodontal tissues.
Aim 1 : Using an animal model for the first time to determine the effects of anti-inflammatory factor in periodontal pathogenesis including inhibition of differentiation of osteoclasts that directly resorb alveolar bone.
Aim 2 : To determine the therapeutic effect of systemic adiponectin infusion in dampening inflammation and in reconstruction of damaged periodontal tissues in vivo. Combining our experience and the expert assistance from Drs. Salomon Amar at Boston University and Gerard Karsenty at Columbia University, the completion of this novel project will definitely provide an advanced bioengineering-based tool to allow precise and predictable control of inflammatory resolution and reconstruction of damaged periodontal tissues.

Public Health Relevance

Prevalent type II diabetes mellitus and obesity predispose patients to refractory periodontitis leading to tooth loss, and the inflammatory factors released from periodontal foci enhance and accelerate the formers. Adiponectin, a fat tissue derived hormone, will prove to be a potent bona fide therapeutic molecule, for the first time, to break the vicious cycle and to provide a novel, unique and efficient remedy for treating this devastating and sometimes rampant disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE021464-02S1
Application #
8517252
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Wan, Jason
Project Start
2011-07-20
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$202,051
Indirect Cost
$78,563
Name
Tufts University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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
Yu, Liming; Tu, Qisheng; Han, Qianqian et al. (2015) Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes. Stem Cells 33:240-52
Han, Qianqian; Yang, Pishan; Wu, Yuwei et al. (2015) Epigenetically Modified Bone Marrow Stromal Cells in Silk Scaffolds Promote Craniofacial Bone Repair and Wound Healing. Tissue Eng Part A 21:2156-65
Zhang, Lan; Meng, Shu; Tu, Qisheng et al. (2014) Adiponectin ameliorates experimental periodontitis in diet-induced obesity mice. PLoS One 9:e97824
Wu, Yuwei; Tu, Qisheng; Valverde, Paloma et al. (2014) Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice. Am J Physiol Endocrinol Metab 306:E1418-30
Zhang, W; Zhu, C; Wu, Y et al. (2014) VEGF and BMP-2 promote bone regeneration by facilitating bone marrow stem cell homing and differentiation. Eur Cell Mater 27:1-11; discussion 11-2
Yan, S G; Zhang, J; Tu, Q et al. (2013) Transcription factor and bone marrow stromal cells in osseointegration of dental implants. Eur Cell Mater 26:263-70; discussion 270-1
Luo, En; Hu, Jing; Bao, Chongyun et al. (2012) Sustained release of adiponectin improves osteogenesis around hydroxyapatite implants by suppressing osteoclast activity in ovariectomized rabbits. Acta Biomater 8:734-43
Zhang, Jin; Tu, Qisheng; Bonewald, Lynda F et al. (2011) Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res 26:1953-63
Zhang, Wenjie; Wang, Xiuli; Wang, Shaoyi et al. (2011) The use of injectable sonication-induced silk hydrogel for VEGF(165) and BMP-2 delivery for elevation of the maxillary sinus floor. Biomaterials 32:9415-24

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