Diabetes-enhanced Experimental Periodontitis

Summary

Principal Investigator: Dana Graves
Affiliation: New Jersey
Country: USA
Abstract: Type 2 diabetes significantly increases the risk and severity of periodontal disease. In humans two different models have been proposed for periodontal disease, a chronic continuous model and a random burst model. Current evidence does not rule out one or the other. We will use a ligature induced model of periodontal bone loss in the rat that exhibits features consistent with the random burst model. The ligature facilitates bacterial invasion of connective tissue leading to an increase in cytokine expression, loss of connective tissue attachment, inflammatory cell recruitment close to bone and alveolar bone resorption. Preliminary data indicate that diabetes significantly alters the progression of periodontal destruction in the rat ligature model in a way that is consistent with the known impact of diabetes on the human periodontium. When ligatures are removed there is a period of bone formation associated with osseous coupling that is significantly reduced in type 2 Zucker diabetic fatty rats compared to genetically matched normoglycemic lean controls. A significant advantage of this model is that the period of bone resorption and formation are both known and can be quantified separately. Thus, the two critical variables needed for the studies below can be accurately assessed. In order to maintain bone mass coupling ensures that bone formation follows resorption. It is possible that diabetes enhances alveolar bone loss by suppression of coupling due to diabetes-impaired bone formation. Thus, we will focus on a previously unreported aspect, that diabetes interferes with the formation of new alveolar bone following an episode of bone resorption. The goal of the proposed studies is to investigate a hypothesis that diabetes through enhanced production of TNF-D increases apoptosis and thereby interferes with coupling of alveolar bone resorption and formation. Aim 1 will investigate whether uncoupling in the periodontium of diabetic animals is due to enhanced levels of TNF-D. These studies will use a TNF-specific inhibitor, etanercept applied by i.p. injection to study the role of TNF-Q Aim 2 will determine whether diabetes enhanced apoptosis represents a functionally significant mechanism for uncoupling of bone formation and resorption in the periodontium. These studies will use i.p. injection of a caspase inhibitor to block apoptosis during bone formation following an episode of periodontal bone resorption in the rat ligature model. Aim 3 will study whether TNF plays a critical role in diabetes enhanced fibroblast apoptosis, diabetes altered gene expression determined by mRNA profiling and matrix metalloproteinase activity. These studies will use the rat model and TNF blocker described in Aim 1.
Funding Period: 2007-07-01 - 2012-06-30
more information: NIH RePORT

Top Publications

  1. ncbi The use of rodent models to investigate host-bacteria interactions related to periodontal diseases
    Dana T Graves
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Clin Periodontol 35:89-105. 2008
  2. ncbi P. gingivalis and E. coli lipopolysaccharides exhibit different systemic but similar local induction of inflammatory markers
    Rongkun Liu
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Periodontol 79:1241-7. 2008
  3. ncbi Cytokines that promote periodontal tissue destruction
    Dana Graves
    Division of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, 100 E Newton Street, Boston, MA 02118, USA
    J Periodontol 79:1585-91. 2008
  4. ncbi The transcription factor ST18 regulates proapoptotic and proinflammatory gene expression in fibroblasts
    Julia Yang
    Boston University School of Dental Medicine, 700 Albany St W 202 D, Boston, MA 02118, USA
    FASEB J 22:3956-67. 2008
  5. ncbi Activation of the acquired immune response reduces coupled bone formation in response to a periodontal pathogen
    Yugal Behl
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Immunol 181:8711-8. 2008
  6. ncbi FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats
    Yugal Behl
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts, USA
    Diabetes 58:917-25. 2009
  7. ncbi High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing
    Jazia Alblowi
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts, USA
    Am J Pathol 175:1574-85. 2009
  8. ncbi Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1)
    M F Siqueira
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA, USA
    Diabetologia 53:378-88. 2010

Scientific Experts

  • Dana Graves
  • Yugal Behl
  • Tesfahun Desta
  • M F Siqueira
  • Jazia Alblowi
  • Michelle Siqueira
  • Julia Yang
  • Rongkun Liu
  • J Yang
  • Y Behl
  • M Alikhani
  • C Braasch
  • J Li
  • L Chehab
  • N Krothpali
  • T Desta
  • T Chino
  • Nanarao Krothapalli
  • Barbara Nikolajczyk
  • Jason Conn
  • Rayyan A Kayal
  • Louis Gerstenfeld
  • Padmaja Krothapalli
  • Thomas A Einhorn
  • Sayon Roy
  • Erin McKenzie
  • Jody McLean
  • Michelle Siqueria
  • Markos Raptis
  • Dan Faibish
  • Michelle F Siqueira
  • Javier Ortiz
  • Mani Alikhani
  • Jingchao Li
  • Richard P Darveau

Detail Information

Publications8

  1. ncbi The use of rodent models to investigate host-bacteria interactions related to periodontal diseases
    Dana T Graves
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Clin Periodontol 35:89-105. 2008
    ....
  2. ncbi P. gingivalis and E. coli lipopolysaccharides exhibit different systemic but similar local induction of inflammatory markers
    Rongkun Liu
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Periodontol 79:1241-7. 2008
    ..gingivalis lipopolysaccharide (PgLPS), PgLPS(1435)(/1449) and PgLPS(1690), exhibit differences in their capacity to stimulate systemic versus local responses compared to Escherichia coli lipopolysaccharide (LPS)...
  3. ncbi Cytokines that promote periodontal tissue destruction
    Dana Graves
    Division of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, 100 E Newton Street, Boston, MA 02118, USA
    J Periodontol 79:1585-91. 2008
    ....
  4. ncbi The transcription factor ST18 regulates proapoptotic and proinflammatory gene expression in fibroblasts
    Julia Yang
    Boston University School of Dental Medicine, 700 Albany St W 202 D, Boston, MA 02118, USA
    FASEB J 22:3956-67. 2008
    ..Taken together, these studies demonstrate that the transcription factor ST18/NZF3 regulates the mRNA levels of proapoptotic and proinflammatory genes in revealing a previously unrecognized function...
  5. ncbi Activation of the acquired immune response reduces coupled bone formation in response to a periodontal pathogen
    Yugal Behl
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Immunol 181:8711-8. 2008
    ..These studies give insight into inflammatory bone diseases such as periodontal disease and arthritis were the formation of lytic lesions occurs in conjunction with deficient bone formation and activation of an acquired immune response...
  6. ncbi FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats
    Yugal Behl
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts, USA
    Diabetes 58:917-25. 2009
    ..To investigate early events leading to microvascular cell loss in diabetic retinopathy...
  7. ncbi High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing
    Jazia Alblowi
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts, USA
    Am J Pathol 175:1574-85. 2009
    ....
  8. ncbi Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1)
    M F Siqueira
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA, USA
    Diabetologia 53:378-88. 2010
    ..The role of TNF-alpha in impaired wound healing in diabetes was examined by focusing on fibroblasts...