One of the goals of periodontal reconstructive therapy is to establish treatment modalities that predictably restore periodontal tissues, i.e. bone, cementum and a functional periodontal ligament (PDL), lost as a consequence of disease. An attractive approach to determining the required factors and cells for regenerating periodontal tissues is to ascertain the factors necessary for their development. We hypothesize that during formation of the periodontium, bone morphogenetic protein-3 (BMP3) acts as a negative regulator of mineralization and amelogenin acts as a positive regulator of mineralization, through their ability to modulate the expression of bone sialoprotein (BSP) and osteocalcin (OCN), thus allowing for formation of cementum and a functional PDL. This hypothesis is supported by existing data that: 1) amelogenin enhances expression of transcripts fro Cbfal, BSP and OCN, in vitro; 2) ameolgenin null mice lack transcripts for BSP; 3) follicle cells express transcripts for BMP2 and 3; and 4) BMP2 promotes follicle cell differentiation toward a cementoblast/osteoblast phenotype, while BMP3 acts as a negative regulator of mineralization.
Two specific aims will test this hypothesis.
The first aim will establish the signal transduction pathways and transcription factors by which amelogenin regulates follicle cell behavior, in vitro.
The second aim i s targeted at defining the BMP3 signal transduction pathways and transcription factors involved in regulating the balance between maturation of follicle cells toward an osteoblast/cementoblast phenotype and toward PDL fibroblasts. Results from these studies will provide important data as to the regulators of ligament formation versus mineralization. This information is necessary for designing regenerative therapies based on sound biological principles.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE009532-13A1
Application #
6572586
Study Section
Special Emphasis Panel (ZRG1-GRM (06))
Program Officer
Shum, Lillian
Project Start
1991-01-01
Project End
2007-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
13
Fiscal Year
2003
Total Cost
$286,084
Indirect Cost
Name
University of Washington
Department
Type
Schools of Dentistry
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Zhang, Hai; Tompkins, Kevin; Garrigues, Jacques et al. (2010) Full length amelogenin binds to cell surface LAMP-1 on tooth root/periodontium associated cells. Arch Oral Biol 55:417-25
Fong, H; Foster, B L; Sarikaya, M et al. (2009) Structure and mechanical properties of Ank/Ank mutant mouse dental tissues--an animal model for studying periodontal regeneration. Arch Oral Biol 54:570-6
Nagatomo, Kanako J; Tompkins, Kevin A; Fong, Hanson et al. (2008) Transgenic overexpression of gremlin results in developmental defects in enamel and dentin in mice. Connect Tissue Res 49:391-400
Hakki, Sema S; Wang, Dian; Franceschi, Renny T et al. (2006) Bone sialoprotein gene transfer to periodontal ligament cells may not be sufficient to promote mineralization in vitro or in vivo. J Periodontol 77:167-73
Swanson, Erica C; Fong, Hanson K; Foster, Brian L et al. (2006) Amelogenins regulate expression of genes associated with cementoblasts in vitro. Eur J Oral Sci 114 Suppl 1:239-43; discussion 254-6, 381-2
Nemoto, E; Darveau, R P; Foster, B L et al. (2006) Regulation of cementoblast function by P. gingivalis lipopolysaccharide via TLR2. J Dent Res 85:733-8
Hakki, Sema S; Nohutcu, Rahime M; Hakki, Erdogan E et al. (2005) Dexamethasone and basic-fibroblast growth factor regulate markers of mineralization in cementoblasts in vitro. J Periodontol 76:1550-8
Chun, Yong-Hee P; Foster, Brian L; Lukasavage, Patricia A et al. (2005) Bisphosphonate modulates cementoblast behavior in vitro. J Periodontol 76:1890-900
Fong, Hanson K; Foster, Brian L; Popowics, Tracy E et al. (2005) The crowning achievement: getting to the root of the problem. J Dent Educ 69:555-70
Foster, B L; Somerman, M J (2005) Regenerating the periodontium: is there a magic formula? Orthod Craniofac Res 8:285-91

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