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. pmc Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity
    Rayyan A Kayal
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Bone Miner Res 22:560-8. 2007
  2. ncbi Bacterial infection increases periodontal bone loss in diabetic rats through enhanced apoptosis
    Sandra Pacios
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Am J Pathol 183:1928-35. 2013
  3. pmc Gene expression dynamics during diabetic periodontitis
    O M Andriankaja
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
    J Dent Res 91:1160-5. 2012
  4. pmc Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes
    Alliny S Bastos
    Department of Diagnosis and Surgery, Araraquara School of Dentistry, Universidade Estadual Paulista, 14801 903 Araraquara, Sao Paulo, Brazil
    J Clin Endocrinol Metab 97:E1353-62. 2012
  5. pmc Animal models to study host-bacteria interactions involved in periodontitis
    Dana T Graves
    Department of Periodontics, University of Pennsylvania, Philadelphia, PA, USA
    Front Oral Biol 15:117-32. 2012
  6. pmc Clopidogrel enhances periodontal repair in rats through decreased inflammation
    Leila S Coimbra
    Department of Physiology and Pathology, Faculdade de Odontologia de Araraquara, Unesp Univ Estadual Paulista, Araraquara, Brazil
    J Clin Periodontol 41:295-302. 2014
  7. pmc Apoptosis in gingival overgrowth tissues
    A Kantarci
    Department of Periodontology and Oral Biology, Boston University, Goldman School of Dental Medicine, Boston, MA 02118, USA
    J Dent Res 86:888-92. 2007
  8. pmc Diabetic complications and dysregulated innate immunity
    Dana T Graves
    Boston University School of Dental Medicine, Department of Periodontology and Oral Biology, W 202D, 700 Albany Street, Boston, MA 02118, USA
    Front Biosci 13:1227-39. 2008
  9. pmc Inflammation and uncoupling as mechanisms of periodontal bone loss
    D T Graves
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, USA
    J Dent Res 90:143-53. 2011
  10. pmc Diabetes aggravates periodontitis by limiting repair through enhanced inflammation
    Sandra Pacios
    Department of Periodontics, University of Pennsylvania, 240 S 40th St, Levy 122, Philadelphia, PA 19104, USA
    FASEB J 26:1423-30. 2012

Scientific Experts

  • Dana Graves
  • David A Albert
  • Sayon Roy
  • Michelle F Siqueira
  • Sandra Pacios
  • Jun Kang
  • Rayyan A Kayal
  • Yugal Behl
  • Beatriz de Brito Bezerra
  • Oelisoa Andriankaja
  • Helen Schreiner
  • Daniel H Fine
  • Jazia Alblowi
  • Mani Alikhani
  • Thomas A Einhorn
  • Tesfahun Desta
  • Leila S Coimbra
  • O M Andriankaja
  • Yu Li
  • VINCENT TSIAGBE
  • Alliny S Bastos
  • Bhaskar Ponugoti
  • Jonathan Brown
  • T Desta
  • Nanarao Krothapalli
  • Jody McLean
  • Dan Faibish
  • Louis C Gerstenfeld
  • Julia Yang
  • Rongkun Liu
  • A Kantarci
  • Carlos Rossa
  • Luis C Spolidorio
  • Joao Paulo Steffens
  • Jason Bae
  • Maher Alnammary
  • Carlos Rossa Junior
  • Silvana R P Orrico
  • J Galicia
  • Faizan Alawi
  • Guangyu Dong
  • Tanize do Espirito Santo Faulin
  • F Alawi
  • G Dong
  • Sophia Petrov
  • Niels Olsen C├ómara
  • Hyung Jin Bae
  • Hemal Patel
  • Johnah Galicia
  • Kenneth Gluck
  • Dulcineia Saes Parra Abdalla
  • Amy Ovaydi-Mandel
  • Oelisoa M Andriankaja
  • Ana Paula de Melo Loureiro
  • W Xiao
  • Jill Suttles
  • Michael Martin
  • Huizhi Wang
  • J Li
  • T Chino
  • Barbara Nikolajczyk
  • Jason Conn
  • Louis Gerstenfeld
  • Padmaja Krothapalli
  • Erin McKenzie
  • Michelle Siqueria
  • Markos Raptis
  • Javier Ortiz
  • Jingchao Li
  • Richard P Darveau
  • Sanjeev Kakar
  • P C Trackman
  • H Hasturk
  • Megan A Bauer
  • Brian Allen
  • E Firatli
  • Cataldo W Leone
  • P Augustin
  • M C Sheff
  • Maisa O Al-Sebaei
  • Dimitris Tsatsas
  • Elise F Morgan

Detail Information

Publications29

  1. pmc Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity
    Rayyan A Kayal
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
    J Bone Miner Res 22:560-8. 2007
    ..Increased cartilage turnover was associated with elevated osteoclast numbers, a higher expression of genes that promote osteoclastogenesis, and diminished primary bone formation...
  2. ncbi Bacterial infection increases periodontal bone loss in diabetic rats through enhanced apoptosis
    Sandra Pacios
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Am J Pathol 183:1928-35. 2013
    ..Thus, bacterial infection in diabetic rats stimulates periodontitis, in part through enhanced apoptosis of osteoblastic cells that reduces osseous coupling through a caspase-3-dependent mechanism...
  3. pmc Gene expression dynamics during diabetic periodontitis
    O M Andriankaja
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
    J Dent Res 91:1160-5. 2012
    ....
  4. pmc Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes
    Alliny S Bastos
    Department of Diagnosis and Surgery, Araraquara School of Dentistry, Universidade Estadual Paulista, 14801 903 Araraquara, Sao Paulo, Brazil
    J Clin Endocrinol Metab 97:E1353-62. 2012
    ..Lipid peroxidation (LPO) is increased in diabetes and may be related to modulation of the inflammatory response. LPO levels in patients with diabetes and periodontal disease have not been evaluated...
  5. pmc Animal models to study host-bacteria interactions involved in periodontitis
    Dana T Graves
    Department of Periodontics, University of Pennsylvania, Philadelphia, PA, USA
    Front Oral Biol 15:117-32. 2012
    ..Thus, each of the models described below can be adapted to test discrete components of the pathological process of periodontal disease, but not necessarily all of them...
  6. pmc Clopidogrel enhances periodontal repair in rats through decreased inflammation
    Leila S Coimbra
    Department of Physiology and Pathology, Faculdade de Odontologia de Araraquara, Unesp Univ Estadual Paulista, Araraquara, Brazil
    J Clin Periodontol 41:295-302. 2014
    ..We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury...
  7. pmc Apoptosis in gingival overgrowth tissues
    A Kantarci
    Department of Periodontology and Oral Biology, Boston University, Goldman School of Dental Medicine, Boston, MA 02118, USA
    J Dent Res 86:888-92. 2007
    ..Analysis of data suggests that increased fibroblast proliferation and a simultaneous decrease in apoptosis contribute to gingival overgrowth...
  8. pmc Diabetic complications and dysregulated innate immunity
    Dana T Graves
    Boston University School of Dental Medicine, Department of Periodontology and Oral Biology, W 202D, 700 Albany Street, Boston, MA 02118, USA
    Front Biosci 13:1227-39. 2008
    ..Cause and effect relationship between dysregulation of key components of innate immunity and diabetic complications in many instances have been demonstrated with the use of cytokine blockers and antioxidants...
  9. pmc Inflammation and uncoupling as mechanisms of periodontal bone loss
    D T Graves
    Department of Periodontics, School of Dental Medicine, University of Pennsylvania, USA
    J Dent Res 90:143-53. 2011
    ....
  10. pmc Diabetes aggravates periodontitis by limiting repair through enhanced inflammation
    Sandra Pacios
    Department of Periodontics, University of Pennsylvania, 240 S 40th St, Levy 122, Philadelphia, PA 19104, USA
    FASEB J 26:1423-30. 2012
    ..Thus, diabetes prolongs inflammation and osteoclastogenesis in periodontitis and through TNF limits the normal reparative process by negatively modulating factors that regulate bone...
  11. pmc A long-term siRNA strategy regulates fibronectin overexpression and improves vascular lesions in retinas of diabetic rats
    Sumon Roy
    Department of Medicine and Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA
    Mol Vis 17:3166-74. 2011
    ..We investigated the efficacy of a small interference RNA (siRNA) strategy in mediating the long-term downregulatory effect of fibronectin (FN) overexpression in vivo...
  12. pmc Diabetes and oral disease: implications for health professionals
    David A Albert
    Columbia University College of Dental Medicine, New York, New York 10032, USA
    Ann N Y Acad Sci 1255:1-15. 2012
    ..This report summarizes the scientific presentations of the event...
  13. pmc Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1
    Jonathan Brown
    Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
    J Biol Chem 286:44295-305. 2011
    ..These findings identify a novel signaling pathway by which mTORC2 regulates the TLR-mediated inflammatory response through its ability to regulate FoxO1...
  14. pmc Aggregatibacter actinomycetemcomitans infection enhances apoptosis in vivo through a caspase-3-dependent mechanism in experimental periodontitis
    Jun Kang
    Department of Periodontology, School and Hospital of Stomatology, Peking University, Beijing, China
    Infect Immun 80:2247-56. 2012
    ..Antibiotics had a more pronounced effect on many of these parameters in diabetic than in normoglycemic rats, suggesting a deficiency in the capacity of diabetic animals to resist infection...
  15. pmc FOXO1 modulates osteoblast differentiation
    Michelle F Siqueira
    Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
    Bone 48:1043-51. 2011
    ..These findings indicate that FOXO1 plays an important role in promoting osteoblast differentiation and suppressing proliferation in differentiating cells...
  16. pmc Role of forkhead transcription factors in diabetes-induced oxidative stress
    Bhaskar Ponugoti
    School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 6030, USA
    Exp Diabetes Res 2012:939751. 2012
    ..They are induced by oxidative stress and contribute to ROS-induced cell damage and apoptosis. In this paper, we discuss the role of FOXO transcription factors in mediating oxidative stress-induced cellular response...
  17. pmc Altered fibroblast proliferation and apoptosis in diabetic gingival wounds
    T Desta
    Department of Periodontics, NJDS UMDNJ, 110 Bergen Street, Newark, NJ 07101 1709, USA
    J Dent Res 89:609-14. 2010
    ..05). The results suggest that diabetes may decrease fibroblast numbers through increased apoptosis and reduced proliferation, both of which may be mediated through increased activation of FOXO1...
  18. pmc FOXO1 plays an essential role in apoptosis of retinal pericytes
    Mani Alikhani
    Department of Orthodontics, New York University, College of Dentistry, New York, NY, USA
    Mol Vis 16:408-15. 2010
    ....
  19. pmc TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1
    Rayyan A Kayal
    Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA, USA
    J Bone Miner Res 25:1604-15. 2010
    ..Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-alpha, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation...
  20. pmc A.actinomycetemcomitans-induced periodontal disease promotes systemic and local responses in rat periodontium
    Beatriz de Brito Bezerra
    Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, Sao Paulo, Brazil
    J Clin Periodontol 39:333-41. 2012
    ..To characterize the histologic and cellular response to A. actinomycetemcomitans (Aa) infection...
  21. pmc 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
    ....
  22. pmc 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)...
  23. 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
    ....
  24. pmc 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...
  25. pmc 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...
  26. pmc 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
    ....
  27. pmc 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...
  28. pmc 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...