Periodontal disease or periodontitis is characterized with inflammation and bone loss due to oral infection. Importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for diabetes, heart diseases, oral cancer, and other systemic diseases. Increased periodontitis is associated with aging, and it represents a significant public concern in the aging population. The mouse model of periodontitis suggests that aging promotes microbial colonization, disease susceptibility, periodontal inflammation and bone loss. However, how aging affects the onset and progression of periodontitis is not fully understood. Peroxisome proliferator-activated receptor ? coactivators 1? (PGC-1?; encoded by Ppargc1?, also known as Pgc-1?) is a master regulator of mitochondrial biogenesis and oxidative metabolism in skeletal muscle, liver, brain and the heart. PGC-1? has been shown to interplay with the NF-?B pathway in skeletal muscle and cardiac cells. During the last funding period, we showed that the immune transcription factor nuclear factor kappa B (NF-?B) played a critical role in bone loss of periodontitis and osteoporosis. Although it is well known that loss of PGC- 1? is associated with increased ROS, aging and chronic inflammation, its role in periodontal inflammation and bone homeostasis is largely unexplored. Therefore, we explored the role of PGC-1? in periodontitis and osteoporotic bone loss. Unexpectedly, we found that PGC-1? was abundantly expressed in monocytes and macrophages, but its expression levels were downregulated with aging. Importantly, genetic studies revealed that loss of PGC-1? significantly increased periodontal inflammation and alveolar bone loss induced by oral infection. Additionally, we found that loss of PGC-1? intrinsically enhanced the expression of pro-inflammatory cytokines in macrophages and osteoclastogenesis by enhancing NF-?B activation in vitro. Based on these exciting novel discoveries, in this competing renewal, we hypothesize that PGC-1? plays a critical role in control of periodontal inflammation and alveolar bone loss in periodontitis by inhibiting NF-?B. Loss of PGC-1? not only promotes the expression of inflammatory mediators, but also enhances osteoclastogenesis and bone resorption. To test our hypothesis, we propose the following three specific aims: 1) Determine whether loss of PGC-1? in monocytes/macrophages exacerbates periodontal inflammation and alveolar bone loss in periodontitis by enhancing NF-?B; 2) Determine if induction of PGC-1? can attenuate periodontal inflammation and alveolar bone loss in periodontitis by inhibiting NF-?B; and 3) Explore the molecular mechanisms by which PGC-1? regulates periodontal inflammation and osteoclastogenesis through NF-?B. New findings from our studies may identify a novel factor that regulates periodontal inflammation and bone loss in periodontitis, and have important implications in the prevention and treatment of periodontitis.

Public Health Relevance

Our application is to examine how the transcriptional co-activator PGC-1? regulates inflammation and bone loss in gum diseases (periodontal diseases). The discoveries from this study will have important implications in developing novel biological strategies for preventing or treating gum diseases and inflammatory bone diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019412-11
Application #
9455702
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Wan, Jason
Project Start
2008-09-08
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yu, Bo; Huo, Lihong; Liu, Yunsong et al. (2018) PGC-1? Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ. Cell Stem Cell 23:615-623
Yu, Bo; Huo, Lihong; Liu, Yunsong et al. (2018) PGC-1? Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ. Cell Stem Cell 23:193-209.e5
Hong, Christine; Song, Dayoung; Lee, Dong-Keun et al. (2017) Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel. Proc Natl Acad Sci U S A 114:E7218-E7225
Tarapore, Rohinton S; Lim, Jason; Tian, Chen et al. (2016) NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression. J Bone Miner Res 31:52-64
Yu, Bo; Wang, Cun-Yu (2016) Osteoporosis: The Result of an 'Aged' Bone Microenvironment. Trends Mol Med 22:641-644
Deng, Peng; Chen, Qian-Ming; Hong, Christine et al. (2015) Histone methyltransferases and demethylases: regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells. Int J Oral Sci 7:197-204
Park, Hyun Woo; Kim, Young Chul; Yu, Bo et al. (2015) Alternative Wnt Signaling Activates YAP/TAZ. Cell 162:780-94
Pacios, Sandra; Xiao, Wenmei; Mattos, Marcelo et al. (2015) Osteoblast Lineage Cells Play an Essential Role in Periodontal Bone Loss Through Activation of Nuclear Factor-Kappa B. Sci Rep 5:16694
Alvarez, Ruth; Lee, Hye-Lim; Wang, Cun-Yu et al. (2015) Characterization of the osteogenic potential of mesenchymal stem cells from human periodontal ligament based on cell surface markers. Int J Oral Sci 7:213-9
Yu, Bo; Chang, Jia; Liu, Yunsong et al. (2014) Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-?B. Nat Med 20:1009-17

Showing the most recent 10 out of 18 publications