About

Helen Schreiner is an Associate Professor in the Department of Oral Biology at Rutgers School of Dental Medicine. Her primary research interests include the identification and characterization of virulence genes of the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa), such as cytolethal distending toxin (cdt), leukotoxin, Aae, and ApiA. She has developed a periodontal disease model in rats for in vivo assessment of bacterial virulence genes and to evaluate host susceptibility to Aa-induced bone loss, aiming to identify host susceptibility genes. Her recent research concentrates on the properties of the Aa outer membrane protein ApiA, and she has worked on comparing Aa strains derived from humans and monkeys, as well as studying the phylology of both types of strains. Dr. Schreiner holds a BA from Barnard College and a PhD from Columbia University in Microbiology.

Research topics

• Ecology
• Biology
• Medicine
• Geography
• Mathematics
• Dentistry
• Genetics
• Paleontology
• Pathology
• Evolutionary biology
• Geometry
• Immunology
• Ancient history
• History

Selected publications

• A Rose by Any Other Name: The Long Intricate History of Localized Aggressive Periodontitis

  Pathogens · 2024-09-29 · 3 citations

  reviewOpen access

  This review addresses the recent World Workshop Consensus Conference (WWCC) decision to eliminate Localized Aggressive Periodontitis (LAgP) in young adults as a distinct form of periodontitis. A “Consensus” implies widespread, if not unanimous, agreement among participants. However, a significant number of attendees were opposed to the elimination of the LAgP classification. The substantial evidence supporting a unique diagnosis for LAgP includes the (1) incisor/molar pattern of disease, (2) young age of onset, (3) rapid progression of attachment and bone loss, (4) familial aggregation across multiple generations, and (5) defined consortium of microbiological risk factors including Aggregatibacter actinomycetemcomitans. Distinctive clinical signs and symptoms of LAgP are presented, and the microbial subgingival consortia that precede the onset of signs and symptoms are described. Using Bradford–Hill guidelines to assess causation, well-defined longitudinal studies support the unique microbial consortia, including A. actinomycetemcomitans as causative for LAgP. To determine the effects of the WWCC elimination of LAgP on research, we searched three publication databases and discovered a clear decrease in the number of new publications addressing LAgP since the new WWCC classification. The negative effects of the WWCC guidelines on both diagnosis and treatment success are presented. For example, due to the localized nature of LAgP, the practice of averaging mean pocket depth reduction or attachment gain across all teeth masks major changes in disease recovery at high-risk tooth sites. Reinstating LAgP as a distinct disease entity is proposed, and an alternative or additional way of measuring treatment success is recommended based on an assessment of the extension of the time to relapse of subgingival re-infection. The consequences of the translocation of oral microbes to distant anatomical sites due to ignoring relapse frequency are also discussed. Additional questions and future directions are also presented.

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• Molecular Analysis of Aggregatibacter actinomycetemcomitans ApiA, a Multi-Functional Protein

  Pathogens · 2024-11-18

  articleOpen access

  Aggregatibacter actinomycetemcomitans ApiA is a trimeric autotransporter outer membrane protein (Omp) that participates in multiple functions, enabling A. actinomycetemcomitans to adapt to a variety of environments. The goal of this study is to identify regions in the apiA gene responsible for three of these functions: auto-aggregation, buccal epithelial cell binding, and complement resistance. Initially, apiA was expressed in Escherichia coli. Finally, wild-type A. actinomycetemcomitans and an apiA-deleted version were tested for their expression in the presence and absence of serum and genes related to stress adaptation, such as oxygen regulation, catalase activity, and Omp proteins. Sequential deletions in specific regions in the apiA gene as expressed in E. coli were examined for membrane proteins, which were confirmed by microscopy. The functional activity of epithelial cell binding, auto-aggregation, and complement resistance were then assessed, and regions in the apiA gene responsible for these functions were identified. A region spanning amino acids 186–217, when deleted, abrogated complement resistance and Factor H (FH) binding, while a region spanning amino acids 28–33 was related to epithelial cell binding. A 13-amino-acid peptide responsible for FH binding was shown to promote serum resistance. An apiA deletion in a clinical isolate (IDH781) was created and tested in the presence and/or absence of active and inactive serum and genes deemed responsible for prominent functional activity related to A. actinomycetemcomitans survival using qRT-PCR. These experiments suggested that apiA expression in IDH781 is involved in global regulatory mechanisms that are serum-dependent and show complement resistance. This is the first study to identify specific apiA regions in A. actinomycetemcomitans responsible for FH binding, complement resistance, and other stress-related functions. Moreover, the role of apiA in overall gene regulation was observed.

  PublisherDOI

• A Rose by Any Other Name: The Long Intricate History of Localized Aggressive Periodontitis

  2024 · 1 citations

  • History
  • Ancient history
  • Medicine

  This narrative review challenges the recent World Workshop Consensus (WWC) conferences failure to classify aggressive periodontitis (AP) in young adults as distinct from adult periodontitis. Deficiencies in the consensus process, results of these deficiencies, and their impact on disease classification are presented. Support for retaining localized aggressive periodontitis (LAgP) in adolescents as a unique disease, focuses on the; 1) age of onset, 2) rate of bone loss in those affected, and 3) unique microbiological etiological associations. Examples of, 1) unique clinical signs and symptoms of LAgP are presented, and 2) the microbial subgingival consortia that precedes these clinical signs and symptoms are described. Tables show, 1) decreased publications for AP since publication of WWC guidelines and 2) Bradford-Hill guidelines that support the unique etiological consortia replicated in clinically well-defined longitudinal studies. The review describes major deficiencies in the WWC as compared to other medically-related well-run consensus conferences that, 1) set pre-conference standards for 70 – 80% agreement of expert participants, and 2) published the dissenting point of view. In contrast, the WWC conference was decided by a mere majority, and never presented the dissenting view. The review concludes that averaging of mean pocket depth reduction, or attachment gain can misrepresent disease and/or success of treatment in aggressive diseases. In contrast, clinical assessment of time to recurrence of subgingival re-infection with possible translocation of oral microbes to distant sites is presented as an alternative measurement of success. Other questions and future directions are presented.

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• Oral microbial interactions from an ecological perspective: a narrative review

  Frontiers in Oral Health · 2023 · 19 citations

  Senior authorCorresponding
  • Ecology
  • Geography
  • Biology

  Landscape ecology is a relatively new field of study within the sub-specialty of ecology that considers time and space in addition to structure and function. Landscape ecology contends that both the configuration (spatial pattern) and the composition (organisms both at the macro and or micro level) of an ecology can change over time. The oral cavity is an ideal place to study landscape ecology because of the variety of landscapes, the dynamic nature of plaque biofilm development, and the easy access to biofilm material. This review is intended to provide some specific clinical examples of how landscape ecology can influence the understanding of oral diseases and act as a supplement to diagnosis and treatment. The purpose of this review is two-fold; (1) to illustrate how landscape ecology can be used to clarify the two most prominent microbiologically induced infections in the oral cavity, and (2) how studies of oral microbiology can be used to enhance the understanding of landscape ecology. The review will distinguish between "habitat" and "niche" in a landscape and extend the concept that a "patch", is the demarcating unit of a habitat within a landscape. The review will describe how; (1) an individual patch, defined by its shape, edges and internal components can have an influence on species within the patch, (2) spatial dynamics over time within a patch can lead to variations or diversities of species within that patch space, and (3) an unwelcoming environment can promote species extinction or departure/dispersion into a more favorable habitat. Understanding this dynamic in relationship to caries and periodontal disease is the focus of this review.

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• Aggregatibacter, a Low Abundance Pathobiont That Influences Biogeography, Microbial Dysbiosis, and Host Defense Capabilities in Periodontitis: The History of a Bug, and Localization of Disease

  Pathogens · 2020 · 38 citations

  • Biology
  • Evolutionary biology
  • Ecology

  plays as a participant in disease. The second part describes landscape ecology in the context of how the host environment shapes the framework of local microbial dysbiosis. We then conjecture as to how the local host response may limit the damage caused by pathobionts. We propose that the host may overcome the constant barrage of a dysbiotic microbiota by confining it to a local tooth site. We conclude speculating that the host response can confine local damage by restricting bacteremic translocation of members of the oral microbiota to distant organs thus constraining morbidity and mortality of the host.

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• NADPH Oxidase Contributes to Resistance against Aggregatibacter actinomycetemcomitans-Induced Periodontitis in Mice

  Infection and Immunity · 2016-11-15 · 8 citations

  articleOpen access

  ABSTRACT Aggregatibacter actinomycetemcomitans is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal A. actinomycetemcomitans infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of A. actinomycetemcomitans -induced periodontitis. NADPH oxidase-deficient (gp91 phox knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with A. actinomycetemcomitans and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection, A. actinomycetemcomitans persisted at significantly higher levels in the murine oral cavities of infected gp91 phox KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91 phox KO mice. Only infected gp91 phox KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control A. actinomycetemcomitans infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis.

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• Role of Exopolysaccharide in Aggregatibacter actinomycetemcomitans–Induced Bone Resorption in a Rat Model for Periodontal Disease

  PLoS ONE · 2015-02-23 · 18 citations

  articleOpen access

  Aggregatibacter actinomycetemcomitans a causative agent of periodontal disease in humans, forms biofilm on biotic and abiotic surfaces. A. actinomycetemcomitans biofilm is heterogeneous in nature and is composed of proteins, extracellular DNA and exopolysaccharide. To explore the role played by the exopolysaccharide in the colonization and disease progression, we employed genetic reduction approach using our rat model of A. actinomycetemcomitans-induced periodontitis. To this end, a genetically modified strain of A. actinomycetemcomitans lacking the pga operon was compared with the wild-type strain in the rat infection model. The parent and mutant strains were primarily evaluated for bone resorption and disease. Our study showed that colonization, bone resorption/disease and antibody response were all elevated in the wild-type fed rats. The bone resorption/disease caused by the pga mutant strain, lacking the exopolysaccharide, was significantly less (P < 0.05) than the bone resorption/disease caused by the wild-type strain. Further analysis of the expression levels of selected virulence genes through RT-PCR showed that the decrease in colonization, bone resorption and antibody titer in the absence of the exopolysaccharide might be due to attenuated levels of colonization genes, flp-1, apiA and aae in the mutant strain. This study demonstrates that the effect exerted by the exopolysaccharide in A. actinomycetemcomitans-induced bone resorption has hitherto not been recognized and underscores the role played by the exopolysaccharide in A. actinomycetemcomitans-induced disease.

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• Lactoferrin Knockout Mice Demonstrates Greater Susceptibility to <i>Aggregatibacter actinomycetemcomitans</i>–Induced Periodontal Disease

  Journal of Periodontology · 2013-01-17 · 27 citations

  article

  BACKGROUND: Among the innate defense mechanisms in the oral cavity, lactoferrin (LF) is a vital antimicrobial that can modify the host response against periodontopathogens. Aggregatibacter actinomycetemcomitans is the main periodontopathogen of localized aggressive periodontitis. The aim of this study is to evaluate the role of LF during A. actinomycetemcomitans-induced periodontitis. METHODS: Differences in the expression levels of cytokines, chemokines, chemokine receptors, and bone loss markers between wild-type (WT) and LF knockout mice (LFKO(-/-)) were evaluated by real time-PCR. Serum IgG and LF levels were quantified by ELISA. Alveolar bone loss among the groups was estimated by measuring the distance from cemento-enamel junction (CEJ) to the alveolar bone crest (ABC) at 20 molar sites. RESULTS: Oral infection with A. actinomycetemcomitans increased LF levels in periodontal tissue (P = 0.01) and saliva (P = 0.0004) of wild-type infected (WTI) mice compared to wild-type control mice. Pro-inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12 were increased in the infected LF knockout (LFKO(-/-)I) mice compared to the WTI mice, whereas the anti-inflammatory cytokines IL-4 and IL-10 were decreased. Chemokines and chemokine receptors showed different expression patterns between WTI and LFKO(-/-)I mice. The LFKO(-/-)I mice developed increased bone loss (P = 0.002), in conjunction with increased expression of receptor activator of nuclear factor-κB ligand and decrease in osteoprotegerin, compared to WTI mice. CONCLUSIONS: These results demonstrate that the infected LFKO(-/-) mice were more susceptible to A. actinomycetemcomitans-induced alveolar bone loss, with different patterns of immune responses compared to those of WTI mice.

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• A Comparison of Aggregatibacter actinomycetemcomitans (Aa) Virulence Traits in a Rat Model for Periodontal Disease

  PLoS ONE · 2013-07-23 · 17 citations

  articleOpen access1st authorCorresponding

  Our aim was to explore the effects of Cytolethal Distending toxin (Cdt) in a well established rat model of periodontal disease where leukotoxin (LtxA) was thought to have no known effect. In vitro studies, were used to assess CdtB activity using Aa Leukotoxin as a negative control. These studies showed that both CdtB and LtxA (unexpectedly) exerted significant effects on CD4(+) T cells. As a result we decided to compare the effects of these two prominent Aa virulence factors on bone loss using our rat model of Aa-induced periodontitis. In this model, Aa strains, mutant in cdtB and ltxA, were compared to their parent non-mutant strains and evaluated for colonization, antibody response to Aa, bone loss and disease. We found that bone loss/disease caused by the ltxA mutant strain, in which cdtB was expressed, was significantly less (p<0.05) than that due to the wild type strain. On the other hand, the disease caused by cdtB mutant strain, in which ltxA was expressed, was not significantly different from the wild type strain. This data indicates that Aa LtxA exerts a greater effect on bone loss than Cdt in this rat model of periodontal disease and supports the utility of this model to dissect specific virulence factors as they relate to immunopathology in studies of Aa-induced disease.

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• Bacterial Infection Increases Periodontal Bone Loss in Diabetic Rats through Enhanced Apoptosis

  American Journal Of Pathology · 2013-10-08 · 74 citations

  articleOpen access

  Periodontal disease is the most common osteolytic disease in humans and is significantly increased by diabetes mellitus. We tested the hypothesis that bacterial infection induces bone loss in diabetic animals through a mechanism that involves enhanced apoptosis. Type II diabetic rats were inoculated with Aggregatibacter actinomycetemcomitans and treated with a caspase-3 inhibitor, ZDEVD-FMK, or vehicle alone. Apoptotic cells were measured with TUNEL; osteoblasts and bone area were measured in H&E sections. New bone formation was assessed by labeling with fluorescent dyes and by osteocalcin mRNA levels. Osteoclast number, eroded bone surface, and new bone formation were measured by tartrate-resistant acid phosphatase staining. Immunohistochemistry was performed with an antibody against tumor necrosis factor-α. Bacterial infection doubled the number of tumor necrosis factor-α–expressing cells and increased apoptotic cells adjacent to bone 10-fold (P < 0.05). Treatment with caspase inhibitor blocked apoptosis, increased the number of osteoclasts, and eroded bone surface (P < 0.05); yet, inhibition of apoptosis resulted in significantly greater net bone area because of an increase in new bone formation, osteoblast numbers, and an increase in bone coupling. 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. Periodontal disease is the most common osteolytic disease in humans and is significantly increased by diabetes mellitus. We tested the hypothesis that bacterial infection induces bone loss in diabetic animals through a mechanism that involves enhanced apoptosis. Type II diabetic rats were inoculated with Aggregatibacter actinomycetemcomitans and treated with a caspase-3 inhibitor, ZDEVD-FMK, or vehicle alone. Apoptotic cells were measured with TUNEL; osteoblasts and bone area were measured in H&E sections. New bone formation was assessed by labeling with fluorescent dyes and by osteocalcin mRNA levels. Osteoclast number, eroded bone surface, and new bone formation were measured by tartrate-resistant acid phosphatase staining. Immunohistochemistry was performed with an antibody against tumor necrosis factor-α. Bacterial infection doubled the number of tumor necrosis factor-α–expressing cells and increased apoptotic cells adjacent to bone 10-fold (P < 0.05). Treatment with caspase inhibitor blocked apoptosis, increased the number of osteoclasts, and eroded bone surface (P < 0.05); yet, inhibition of apoptosis resulted in significantly greater net bone area because of an increase in new bone formation, osteoblast numbers, and an increase in bone coupling. 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. Diabetes is a chronic inflammatory disease characterized by hyperglycemia that affects 26 million Americans.1Gong Z. Muzumdar R.H. Pancreatic function, type 2 diabetes, and metabolism in aging.Int J Endocrinol. 2012; 2012: 320482Crossref PubMed Scopus (88) Google Scholar Diabetes has several complications, such as cardiovascular, renal, microvascular, and periodontal diseases. Periodontal disease is one of the most common forms of osteolytic bone disease and one of the most frequent complications of the diabetes.2Lamster I.B. Lalla E. Borgnakke W.S. Taylor G.W. The relationship between oral health and diabetes mellitus.J Am Dent Assoc. 2008; 139: 19S-24SAbstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar Recent research suggests that the relationship between periodontitis and diabetes is reciprocal.3Lalla E. Papapanou P.N. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases.Nat Rev Endocrinol. 2011; 7: 738-748Crossref PubMed Scopus (564) Google Scholar, 4Bascones-Martinez A. Arias-Herrera S. Criado-Camara E. Bascones-Ilundain J. Bascones-Ilundain C. Periodontal disease and diabetes.Adv Exp Med Biol. 2012; 771: 76-87PubMed Google Scholar People with diabetes are more susceptible to periodontitis, and periodontitis may affect serum glucose levels and contribute to progression of diabetes.5Gurav A.N. Periodontitis and insulin resistance: casual or causal relationship?.Diabetes Metab J. 2012; 36: 404-411Crossref PubMed Scopus (45) Google Scholar Diabetes may contribute to periodontitis because of its effect on inflammation.6Otomo-Corgel J. Pucher J.J. Rethman M.P. Reynolds M.A. State of the science: chronic periodontitis and systemic health.J Evid Based Dent Pract. 2012; 12: 20-28Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 7Nassar H. Kantarci A. van Dyke T.E. Diabetic periodontitis: a model for activated innate immunity and impaired resolution of inflammation.Periodontol 2000. 2007; 43: 233-244Crossref PubMed Scopus (86) Google Scholar Despite being triggered by bacterial infection, periodontal bone loss is tied to the inflammatory host response, which leads to the generation of prostaglandins and cytokines that stimulate osteoclastogenesis and periodontal bone loss.8Li Q. Valerio M.S. Kirkwood K.L. MAPK usage in periodontal disease progression.J Signal Transduct. 2012; 2012: 308943Crossref PubMed Google Scholar Several of the detrimental aspects of periodontal disease have recently been shown to be mediated by elevated levels of tumor necrosis factor-α (TNF-α).9Garlet G.P. Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints.J Dent Res. 2010; 89: 1349-1363Crossref PubMed Scopus (464) Google Scholar, 10Graves D.T. Li J. Cochran D.L. Inflammation and uncoupling as mechanisms of periodontal bone loss.J Dent Res. 2011; 90: 143-153Crossref PubMed Scopus (204) Google Scholar TNF-α is a proinflammatory cytokine produced by leukocytes and other cell types.11Croft M. Benedict C.A. Ware C.F. Clinical targeting of the TNF and TNFR superfamilies.Nat Rev Drug Discov. 2013; 12: 147-168Crossref PubMed Scopus (315) Google Scholar Enhanced TNF-α levels have been directly linked to cellular changes in diabetic retinopathy, deficits in wound healing, and diabetes-enhanced periodontitis.12Behl Y. Krothapalli P. Desta T. Dipiazza A. Roy S. Graves D.T. Diabetes-enhanced tumor necrosis factor-{alpha} production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy.Am J Pathol. 2008; 172: 1411-1418Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 13Pacios S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar, 14Kayal R.A. Siqueira M. Alblowi J. McLean J. Krothapalli N. Faibish D. Einhorn T.A. Gerstenfeld L.C. Graves D.T. TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1.J Bone Miner Res. 2010; 25: 1604-1615Crossref PubMed Scopus (125) Google Scholar Some of the detrimental effects of diabetes-enhanced TNF-α levels may be because of the induction of cell death by triggering caspase activity. Caspases are a family of cysteine proteases that can act as either initiators (caspases 2, 8, and 9) or executioners (caspases 3, 6, and 7) of apoptosis.15Chowdhury I. Tharakan B. Bhat G.K. Caspases: an update.Comp Biochem Physiol B Biochem Mol Biol. 2008; 151: 10-27Crossref PubMed Scopus (300) Google Scholar Caspase-3 appears to play a central role in bacteria and lipopolysaccharide-mediated apoptosis.16Al-Mashat H.A. Kandru S. Liu R. Behl Y. Desta T. Graves D.T. Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing.Diabetes. 2006; 55: 487-495Crossref PubMed Scopus (77) Google Scholar, 17Alikhani M. Alikhani Z. He H. Liu R. Popek B.I. Graves D.T. Lipopolysaccharides indirectly stimulate apoptosis and global induction of apoptotic genes in fibroblasts.J Biol Chem. 2003; 278: 52901-52908Crossref PubMed Scopus (58) Google Scholar In addition, it has been shown that TNF-α can stimulate the expression of several pro-apoptotic genes, many of which are regulated by the pro-apoptotic transcription factor, forkhead box-O1 (FOXO1).18Ponugoti B. Dong G. Graves D.T. Role of forkhead transcription factors in diabetes-induced oxidative stress.Exp Diabetes Res. 2012; 2012: 939751Crossref PubMed Scopus (151) Google Scholar The functional role of apoptosis in pathological processes can be studied with caspase inhibitors, which are small peptides that block the activity of well-defined caspases.19Callus B.A. Vaux D.L. Caspase inhibitors: viral, cellular and chemical.Cell Death Differ. 2007; 14: 73-78Crossref PubMed Scopus (156) Google Scholar These inhibitors have been used in animal models to attenuate cell death and diminish tissue damage in ischemic conditions, sepsis, and other pathological processes.20Concha N.O. Abdel-Meguid S.S. Controlling apoptosis by inhibition of caspases.Curr Med Chem. 2002; 9: 713-726Crossref PubMed Scopus (50) Google Scholar, 21Wilson S.E. Mohan R.R. Hong J. Lee J. Choi R. Liu J.J. Apoptosis in the cornea in response to epithelial injury: significance to wound healing and dry eye.Adv Exp Med Biol. 2002; 506: 821-826Crossref PubMed Scopus (2) Google Scholar Other studies using caspase inhibitors have shown that part of the detrimental effect of diabetes on healing after infection is the result of increased fibroblast or osteoblast apoptosis.16Al-Mashat H.A. Kandru S. Liu R. Behl Y. Desta T. Graves D.T. Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing.Diabetes. 2006; 55: 487-495Crossref PubMed Scopus (77) Google Scholar, 22Siqueira M.F. Li J. Chehab L. Desta T. Chino T. Krothpali N. Behl Y. Alikhani M. Yang J. Braasch C. Graves D.T. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1).Diabetologia. 2010; 53: 378-388Crossref PubMed Scopus (163) Google Scholar To understand how diabetes may affect periodontal bone loss through apoptosis, we used a caspase-3/7 inhibitor in a type 2 Goto-Kakizaki (GK) diabetic rat model of periodontal disease induced by bacterial infection. The aim of this study was to determine how apoptosis of osteoblasts contributed to periodontal bone loss by its effect on bone formation in diabetic animals. GK male and female rats were purchased from Charles River Laboratories (Wilmington, MA). The GK rat naturally develops type 2 diabetes mellitus at the age of approximately 12 weeks. Rats were housed in separate cages and fed powdered food (Laboratory Rodent Meal Diet 5001; Purina Mills Feeds, St. Louis, MO). When glucose levels were >220 mg/dL, and glycated hemoglobin levels were >7.0%, they were classified as diabetic. All animal procedures were approved by the Institutional Animal Care and Use Committee. Diabetic (GK) rats received antibiotics ad libitum in their drinking water for 4 days (20 mg kanamycin and 20 mg ampicillin) and were swabbed with a 0.12% chlorhexidine gluconate rinse during the past 2 days (Procter and Gamble, Cincinnati, OH) to facilitate colonization by Aggregatibacter days and for A. actinomycetemcomitans cells A. a A. actinomycetemcomitans New were by oral to diabetic (GK) and A. actinomycetemcomitans cells was in their food a for as K. D. B.A. genes of actinomycetemcomitans are for in a rat A. 2003; PubMed Scopus Google Scholar Some received or caspase-3 inhibitor 4 after the as for 4 days to A. actinomycetemcomitans K. D. B.A. genes of actinomycetemcomitans are for in a rat A. 2003; PubMed Scopus Google Scholar These animals were 1 and 2 after the of the and after A. actinomycetemcomitans Caspase-3 inhibitor, was by at 4 and rats were 1 or 2 treated with caspase inhibitor were with the of Immunohistochemistry was performed with an antibody against TNF-α The number of cells adjacent to bone was as we have S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar at Apoptotic cells were by Apoptosis was measured with with an antibody to apoptotic The number of apoptotic cells was at with an using in a adjacent to bone and in were performed with to animals were as cells in of bone in sections. eroded and new bone formation were measured with tartrate-resistant acid phosphatase as S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar Bone was measured by using St. Louis, and fluorescent staining. was by at 4 and was labeling of new bone formation was measured by in sections. The area between the two fluorescent was D.L. He Yang Liu L. of bone of B. 2012; PubMed Scopus Google Scholar Bone coupling was as the bone number of or the of eroded Bone area was measured as the area by were performed with to animals was from the of the and as S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar mRNA levels of osteocalcin were assessed by using and for osteocalcin were to a The were performed with to animals with and performed with were performed using 20 of with was used to the between at a and to from with the other The significance was at < Apoptosis was measured as the number of apoptotic cells and the number of apoptotic cells I.B. Lalla E. Borgnakke W.S. Taylor G.W. The relationship between oral health and diabetes mellitus.J Am Dent Assoc. 2008; 139: 19S-24SAbstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar in the periodontal adjacent to bone and the bone the number of apoptotic cells was after A. actinomycetemcomitans infection, the of apoptosis increased by approximately in cells adjacent to bone and the bone surface (P < 0.05). The increase in apoptosis with infection can be for by a increase in expression of pro-apoptotic such as in to the cells was and more doubled to at (P < 0.05). Treatment with and caspase-3 inhibitor apoptosis to levels The was shown with the number of cells and In a small effect on Bone is by bone formation in a to as Bone cellular for coupling of bone formation and Biol. 2008; PubMed Scopus Google Scholar In periodontal disease and other bone pathological conditions, bone coupling is D.T. Li J. Cochran D.L. Inflammation and uncoupling as mechanisms of periodontal bone loss.J Dent Res. 2011; 90: 143-153Crossref PubMed Scopus (204) Google Scholar We inhibition of apoptosis the number of osteoblasts after induction of periodontal disease with an increase in apoptosis (P < 0.05). periodontitis with the of antibiotics increased the number of osteoblasts by (P < 0.05). with caspase-3 inhibitor increased the number by at and at with the or inhibitor (P < 0.05). Thus, of the increase in osteoblast be directly tied to apoptosis from with the caspase-3 bone area increased with caspase-3 inhibitor (P < periodontal bone loss is by inhibition of apoptosis in diabetic Periodontitis was induced in GK diabetic rats treated with or caspase-3 inhibitor, as in sections. Bone area was as the area by < a between the and < a with To the of caspase-3 inhibitor on new bone formation was measured with with which used the as a and that the of new bone formation increased diabetic rats were treated with caspase-3 inhibitor (P < Treatment with the in bone the of new bone formation was measured at the by expression of osteocalcin mRNA Diabetic rats osteocalcin mRNA levels at weeks. When diabetic rats were treated with inhibitor, was a increase with the (P < 0.05). new bone formation was assessed using fluorescent in and The of caspase inhibitor increased the of new bone formation by at and at with the at the (P < effect on the of bone bone formation is increased by caspase Periodontitis was induced in GK diabetic which were treated with or caspase-3 inhibitor, as in and New bone formation was measured using fluorescent in sections. The between fluorescent was used to new bone The the between bone and periodontal between periodontal and New bone formation was assessed at and < a between the and < a with the To the effect of caspase-3 inhibitor on bone the number of 6, and the eroded bone surface that activity were Osteoclast and activity increased by approximately after the infection 6, and increase with the with the with caspase inhibitor increased the number of by and eroded bone surface by (P < 0.05). To the of diabetes on bone the of new bone formation by labeling was by an of or eroded bone surface Treatment with antibiotics increase in bone coupling. Treatment with caspase-3 inhibitor significantly increased bone coupling by approximately measured to or by eroded bone surface (P < 0.05). We that diabetes significantly enhanced in the and that the diabetes-enhanced was tied to levels of apoptosis in the and tissue of diabetic S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar, J. B. S. Li Y. H. Graves D.T. Aggregatibacter actinomycetemcomitans infection enhances apoptosis in through a mechanism in 2012; PubMed Scopus (45) Google Scholar In the we the role of levels of apoptosis in diabetic animals to determine its to periodontal bone of bone formation and bone to bone coupling. 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Caspases family are in the of the of Full Text Full Text PDF PubMed Scopus Google Scholar, of caspase-3 activity in apoptotic in Full Text Full Text PDF PubMed Scopus Google Scholar These with in which the number of and their activity were increased caspase-3 is is a greater increase in bone formation that the net effect of apoptosis in diabetic animals is to bone is with other pathological in which and osteoblast apoptosis, through the caspase-3 have been shown to contribute to bone formation and bone in and inflammatory D. J. S. C. M. Caspase inhibitors of in 2006; PubMed Scopus Google Scholar, of apoptosis in 2010; PubMed Scopus Google Scholar We antibiotics to infection on studies in which of antibiotics a of S. and of for 2013; PubMed Scopus Google Scholar In such as the number of in the effect of was small with the of the caspase In diabetes has been shown to have a effect on bone in periodontitis and on of caspase-3 activity in apoptotic in Full Text Full Text PDF PubMed Scopus Google Scholar We that diabetes has an effect on bone through apoptosis of These with that diabetes-enhanced loss of osteoblasts reduces bone coupling. In the of osseous is loss of periodontal which is one of the of new as to how diabetes can affect bone and may contribute to diabetes-enhanced periodontitis and other pathological in which diabetes has a on and impaired fracture M. H. B. K. P. G. D. an role in bone fracture 2013; PubMed Scopus Google Scholar We have recently shown that diabetes-enhanced TNF-α a role in the resolution of periodontal and bone S. Kang J. Galicia J. Gluck K. Patel H. Ovaydi-Mandel A. Petrov S. Alawi F. Graves D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.FASEB J. 2012; 26: 1423-1430Crossref PubMed Scopus (113) Google Scholar, Galicia J. Dong G. Alawi F. Graves D.T. expression during diabetic Dent Res. 2012; PubMed Scopus Google Scholar These with that diabetes-enhanced periodontitis is significantly by elevated levels of and apoptosis. studies may mechanisms by which diabetes leads to enhanced TNF-α which may be in bone coupling. We for in the and for in the in of research that are in the of The of PDF

  PublisherOA PDFDOI

Recent grants

• PGA exopolysaccharide in biofilm formation and pathogenicity of Aggregatibacter a

  NIH · $1.4M · 2012–2018

Frequent coauthors

• Daniel H. Fine

  Rutgers, The State University of New Jersey

  22 shared

• David Furgang

  Rutgers, The State University of New Jersey

  9 shared

• David H. Figurski

  Canberra Hospital

  9 shared

• Vincent K. Tsiagbe

  Rutgers, The State University of New Jersey

  6 shared

• P Goncharoff

  Office of Chief Medical Examiner

  5 shared

• Jun Kang

  Sun Yat-sen University

  5 shared

• Dana T. Graves

  University of Pennsylvania

  5 shared

• Jeffrey B. Kaplan

  American University

  5 shared

Awards & honors

• Rutger Biomedical and Health Sciences Foundation grants (200…