The objective of the proposed research is to further characterize the bone resorptive mediators which stimulate periapical bone destruction following infection of the dental pulp. A rat model will be employed in which pulpal and periapical destruction occurs with predictable kinetics after pulp exposure, permitting the definition of active (rapid) and chronic phases of destruction. Previous studies have implicated cytokines, in particular, interleukin 1 alpha (IL-1alpha), as key mediators in these events. Direct evidence for cytokine gene expression and synthesis in pulp and periapical lesions will be sought, using high sensitivity techniques for small tissue samples. These include polymerase chain reaction (PCR), in situ hybridization, and immunochemistry, in combination with cell identification techniques. Methods of specifically inhibiting the action of IL-1alpha, such as the use of antisense oligomers and an IL-1 receptor antagonist, will be explored. Finally, the general biologic role of inflammatory bone resorption will be explored in a resorption deficient rat model, in order to determine whether resorption is primarily destructive, or whether it may serve to protect the host against more severe consequences, including disseminated infection. These studies will provide definitive information on the mediators which stimulate resorption following infection of the pulp, and will permit the rational design of therapeutic agents which block resorption.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE009018-04
Application #
3222841
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1989-03-15
Project End
1995-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02142
AlShwaimi, Emad; Berggreen, Ellen; Furusho, Hisako et al. (2013) IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction. J Immunol 191:1785-91
Franco, Gilson C N; Kajiya, Mikihito; Nakanishi, Tadashi et al. (2011) Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo. Exp Cell Res 317:1454-64
Sasaki, H; Suzuki, N; Alshwaimi, E et al. (2010) 18*-glycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-*B inactivation in interleukin-10-deficient mice. J Periodontal Res 45:757-63
AlShwaimi, Emad; Purcell, Patricia; Kawai, Toshihisa et al. (2009) Regulatory T cells in mouse periapical lesions. J Endod 35:1229-33
Sasaki, Hajime; Suzuki, Noriyuki; Kent Jr, Ralph et al. (2008) T cell response mediated by myeloid cell-derived IL-12 is responsible for Porphyromonas gingivalis-induced periodontitis in IL-10-deficient mice. J Immunol 180:6193-8
Leshem, Onir; Kashino, Suely S; Goncalves, Reginaldo B et al. (2008) Th1 biased response to a novel Porphyromonas gingivalis protein aggravates bone resorption caused by this oral pathogen. Microbes Infect 10:664-72
Kawai, T; Paster, B J; Komatsuzawa, H et al. (2007) Cross-reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent periodontal bone resorption in a mouse model. Oral Microbiol Immunol 22:208-15
Ernst, C W O; Lee, J E; Nakanishi, T et al. (2007) Diminished forkhead box P3/CD25 double-positive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL+) T cells in bone resorption lesion of periodontal disease. Clin Exp Immunol 148:271-80
Stashenko, Philip; Goncalves, Reginaldo B; Lipkin, Brad et al. (2007) Th1 immune response promotes severe bone resorption caused by Porphyromonas gingivalis. Am J Pathol 170:203-13
Goncalves, Reginaldo B; Leshem, Onir; Bernards, Karen et al. (2006) T-cell expression cloning of Porphyromonas gingivalis genes coding for T helper-biased immune responses during infection. Infect Immun 74:3958-66

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