The overall goal of this project is to develop and validate new strategies for ameliorating tissue destruction of periodontal disease by modulating activity of immune effector cells and/or regulating expression of the cytokine, Receptor Activator of NF-?B Ligand (RANKL). Recent studies demonstrated unequivocally that host immune responses play a key role in activating osteoclasts and promoting bone resorption in periodontal disease. T and B lymphocytes found in periodontal lesions express abundant RANKL, and stimulation of RANKL expression in these lymphocytes in vitro induces osteoclastogenesis. These findings provide a fundamentally new understanding of the mechanism of periodontal disease and support the hypothesis that tissue destruction in periodontal disease can be ameliorated by inhibition of RANKL activity in the immune effector cells. This laboratory has developed, validated and published several inclusive experimental models to characterize the role of host immunity in periodontal disease. These models include: 1) three in vivo rat models to dissect the specific roles of T cells and B cells in mediating periodontal bone resorption in gingival challenge and adoptive transfer of T or B lymphocytes and an infection model of periodontal disease;and 2) two in vitro models for testing human peripheral blood lymphocytes from healthy persons or human gingival mononuclear cell osteoclastogenesis from patients with periodontal disease where these rats experience periodontal bone resorption. The objectives of this study are to determine whether inhibition of RANKL activity reduces periodontal bone resorption, and to characterize the cellular and immunological mechanisms that mediate this process.
Aim 1 is to evaluate mechanisms of preventing or reducing periodontal bone resorption by inhibiting RANKL expression or modulating its activity In vitro and in vivo studies will characterize the effects of inhibiting RANKL directly by antibody and inhibiting the TNF-a-Converting Enzyme (TACE), which is required for RANKL solubilization, with anti-TACE antibody or the known TACE inhibitor, galardin. Outcome measures will include resorption of bone, as measured microscopically, and characterization of bone pit formation;
Aim 2 is to evaluate mechanisms of preventing or reducing periodontal bone resorption by inhibiting signaling pathways that regulate RANKL production by lymphocytes. Studies will characterize the role of two key signaling molecules - TRAF6 and CDK4 - in regulating RANKL expression in activated rat T and B cells in vitro, and will evaluate the effects of blocking these signaling molecules in the three rat models.
Aim 3 is to characterize the inhibitory mechanisms of periodontal bone resorption identified in Aims 1 and 2. in vitro studies will asses the effects of blocking RANKL or inhibiting TACE in healthy human peripheral blood T and B cells, and in gingival tissue mononuclear cells from patients with periodontal disease. Periodontitis, which is responsible for half of all tooth loss in adults, occurs in moderate form in 30% of American adults and in severe form in 5% of adults. The current standard of care is mechanical removal of plaque biofilms. Successful completion of these studies will provide a fundamental understanding of the role of host immune response in mediating bone resorption and may lead to future clinical translational studies of novel strategies for preventing tooth loss in periodontitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE003420-36
Application #
8214538
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
1976-02-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
36
Fiscal Year
2012
Total Cost
$453,467
Indirect Cost
$225,594
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Matsuda, Shinji; Movila, Alexandru; Suzuki, Maiko et al. (2016) A novel method of sampling gingival crevicular fluid from a mouse model of periodontitis. J Immunol Methods 438:21-25
Kanzaki, Hiroyuki; Shinohara, Fumiaki; Suzuki, Maiko et al. (2016) A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma. Sci Rep 6:32259
Chen, W; Gao, B; Hao, L et al. (2016) The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation. J Periodontal Res 51:647-60
Kanzaki, Hiroyuki; Makihira, Seicho; Suzuki, Maiko et al. (2016) Soluble RANKL Cleaved from Activated Lymphocytes by TNF-α-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis. J Immunol 197:3871-3883
Gaffen, S L; Herzberg, M C; Taubman, M A et al. (2014) Recent advances in host defense mechanisms/therapies against oral infectious diseases and consequences for systemic disease. Adv Dent Res 26:30-7
Yu, Xiaoqian; Lin, Jiang; Yu, Qing et al. (2014) Activation of Toll‐like receptor 9 inhibits lipopolysaccharide‐induced receptor activator of nuclear factor kappa‐ B ligand expression in rat B lymphocytes. Microbiol Immunol 58:51-60
Lin, Jiang; Bi, Liangjia; Yu, Xiaoqian et al. (2014) Porphyromonas gingivalis exacerbates ligature-induced, RANKL-dependent alveolar bone resorption via differential regulation of Toll-like receptor 2 (TLR2) and TLR4. Infect Immun 82:4127-34
Han, Xiaozhe; LaRosa, Karen B; Kawai, Toshihisa et al. (2014) DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component. Vaccine 32:297-303
Han, Xiaozhe; Lin, Xiaoping; Yu, Xiaoqian et al. (2013) Porphyromonas gingivalis infection-associated periodontal bone resorption is dependent on receptor activator of NF-κB ligand. Infect Immun 81:1502-9
Jin, Jun-O; Han, Xiaozhe; Yu, Qing (2013) Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. J Autoimmun 40:28-44

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