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G( ) Anaerobes–Reactive CD4 T-Cells Trigger RANKL-Mediated

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G( ) Anaerobes–Reactive CD4 T-Cells Trigger RANKL-Mediated G(؊) Anaerobes–Reactive CD4؉ T-Cells Trigger RANKL-Mediated Enhanced Alveolar Bone Loss in Diabetic NOD Mice Deeqa A. Mahamed,1,2 Annette Marleau,2 Mawadda Alnaeeli,1 Bhagirath Singh,2 Xiaoxia Zhang,1 Joseph M. Penninger,3 and Yen-Tung A. Teng1,2 Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism re- mains unclear. We investigated the contribution of anti- uman periodontal disease is a chronic inflamma- bacterial T-cell–mediated immunity to enhanced alveolar tory disease triggered by infection with specific bone loss during periodontal infection in nonobese subgingival microorganisms. Initially, inflam- diabetic (NOD) mice by oral inoculation with Actino- Hmation and bleeding of the gingival tissue (gin- bacillus actinomycetemcomitans,aG(؊) anaerobe givitis) prevails, followed by destruction of the supporting responsible for juvenile and severe periodontitis. The connective and bone tissues around the tooth (periodon- results show that 1) inoculation with A. actinomycetem- titis), eventually leading to tooth loss. Microbial species comitans in pre-diabetic NOD mice does not alter the such as Actinobacillus actinomycetemcomitans, Por- onset, incidence, and severity of diabetes; 2) after phorymonas gingivalis, Bacteriodes forsythus, and mixed A. actinomycetemcomitans inoculation, diabetic NOD spirochetes have been shown to be involved in the disease mice (blood glucose 200 mg/dl and with severe insuli- > pathogenesis, the development of which is further influ- tis) exhibit significantly higher alveolar bone loss com- pared with pre-diabetic and nondiabetic NOD mice; and enced by the host’s immune system, diet, oral hygiene, and ؉ Ϫ 3) A. actinomycetemcomitans–reactive CD4 T-cells in any genetic predisposition (1,2). The G( ) anaerobe A. diabetic mice exhibit significantly higher proliferation actinomycetemcomitans is responsible for Ͼ90% juvenile and receptor activator of nuclear factor ␬B ligand periodontitis (or aggressive periodontitis [3]). A. actino- (RANKL) expression. When diabetic mice are treated mycetemcomitans–associated periodontitis is marked by with the RANKL antagonist osteoprotegerin (OPG), rapid destruction of bone and connective tissues (4–6), there is a significant reversal of alveolar bone loss, as and this species has also been implicated in life-threaten- well as reduced RANKL expression in A. actinomyce- ing diseases like endocarditis and pneumonia (3,5). To ؉ temcomitans–reactive CD4 T-cells. This study clearly date, many virulence factors (e.g., leukotoxin, adhesins, describes the impact of autoimmunity to anaerobic in- toxins, and immunosuppressive factors [4–6]) have been fection in an experimental periodontitis model of type 1 .؉ identified and studied diabetes. Thus, microorganism-reactive CD4 T-cells T-cells, especially CD4ϩ T-cells, are implicated in peri- and the RANKL-OPG axis provide the molecular basis of odontal inflammation and tissue destruction (7–9) and the advanced periodontal breakdown in diabetes and, may secrete proinflammatory cytokines such as interleu- therefore, OPG may hold therapeutic potential for treat- kin (IL)-6 and tumor necrosis factor (TNF)-␣ (2,7–9). ing bone loss in diabetic subjects at high risk. Diabetes ␬ 54:1477–1486, 2005 Receptor activator of nuclear factor- B (RANK) ligand (RANKL), a member of the TNF ligand super-family, is a recently discovered molecule that links T-cell–mediated immunity and bone remodeling and is expressed by osteo- From the 1Eastman Department of Dentistry and Center for Oral Biology, blasts and bone stromal cells (10–14). Its biological activ- Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, New York; the 2Department of ity involves interactions with RANK on osteoclasts and Microbiology and Immunology, Faculty of Medicine and Dentistry, University osteoclast precursors for their differentiation, activation, of Western Ontario, London, Ontario, Canada; and the 3Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. and survival (10–12). Another player is osteoprotegerin Address correspondence and reprint requests to Dr. Andy Y.-T. Teng, (OPG), secreted by osteoblasts and bone marrow stromal Laboratory of Molecular Microbial Immunity, Eastman Department of Den- cells and functioning by interrupting RANK-RANKL signal- tistry and Center for Oral Biology, Department of Microbiology and Immunol- ogy, School of Medicine and Dentistry, University of Rochester Medical ing by binding to membrane-bound and soluble RANKL Center, Rochester, NY, 14620. E-mail: [email protected]. (s-RANKL [11–13]). OPG transgenic mice are osteope- Received for publication 28 May 2004 and accepted in revised form trotic with defective osteoclast activity, and OPG-deficient 20 January 2005. CLN, cervical lymph node; FACS, fluorescence-activated cell sorter; FITC, mice are severely osteoporotic (12). Moreover, the RANK- fluorescein isothiocyanate; IL, interleukin; OPG, osteoprotegerin; RANK, RANKL interaction also occurs in the immune system, ␬ receptor activator of nuclear factor B; RANKL, RANK ligand; s-RANKL, including lymph node organogenesis and B-cell develop- soluble RANKL; STZ, streptozocin; TNF, tumor necrosis factor. Ϫ/Ϫ © 2005 by the American Diabetes Association. ment as elucidated by the study of RANKL mice The costs of publication of this article were defrayed in part by the payment of page (14,15). In addition, activated and memory T-cells express charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. RANKL in response to bacterial stimulation and thereby DIABETES, VOL. 54, MAY 2005 1477 BONE LOSS AND DIABETES-ASSOCIATED PERIODONTITIS promote osteoclast differentiation and maturation (2,8,11, considered nondiabetic, and mice Ͼ16–20 weeks old with blood glucose levels Ͼ200 mg/dl and insulitis considered diabetic. In addition, serum HbA 15,16). Genetic mutations of RANKL and RANK demon- 1c levels were also monitored. The incidence and age of disease onset in A. strate similar phenotypes in osteoclast development with actinomycetemcomitans–infected versus –noninfected control NOD mice severe osteopetrosis, suggesting that they are essential for were compared throughout the entire experiment. All experimental proce- osteoclastogenesis during bone remodeling (10,12,15). Thus, dures were conducted in accordance with the guidelines of the Canadian RANKL, RANK, and OPG are essential for controlling os- Council on Animal Care and the University Councils on Animal Care and Use teoclast development and functions in bone remodeling. Subcommittee. Type 1 diabetes is an autoimmune disease in which Bacterial oral inoculation and adoptive transfer. A. actinomycetemcomi- tans JP2 (ATCC-29523) strain was purchased from ATCC (Rockville, MD) and insulin-producing pancreatic ␤-cells are destroyed by in- ϩ ϩ grown anaerobically (80% N2, 10% H2, 10% CO2) in tryptic soy broth-yeast filtrating autoreactive T-cells. Both CD4 and CD8 T-cells extract culture broth (TSBYE; Sigma Chemical, St. Louis, MO) supplemented are involved in disease pathogenesis (17,18). Diabetogenic with 0.75% glucose and 0.4% NaHCO3. Six different groups of pre-diabetic, T-cells react to autoantigens such as insulin, GAD65, and nondiabetic, and diabetic NOD mice (n ϭ 10/group) were orally inoculated 9 ␮ ICA512 (insulinoma-associated protein 2) in diabetic pa- with A. actinomycetemcomitans (10 cfu/100- l broth mixed with 2% car- boxymethylcellulose in PBS) two times per week for 3 consecutive weeks as tients and experimental animal models (19). Islet-specific ϩ described (8–9). The mice were then killed at weeks 4 and 8. Age-matched CD4 T-cells isolated from the pancreas and draining NOD mice without bacterial inoculation served as controls (n ϭ 10/group) and lymph nodes secrete predominantly Th1 cytokines (19). were kept under the same conditions. To monitor the incidence of diabetes, a Clinical studies suggest that periodontitis can rapidly pro- separate group of 4- to 6-week-old pre-diabetic NOD mice were inoculated gress to advanced stages in type 1 and type 2 diabetic with A. actinomycetemcomitans two times per week (in 2% carboxymethyl- cellulose) for 3 weeks and monitored for the incidence of diabetes until age 25 patients and is even more adversely exacerbated among weeks. The adoptive transfer experiment was conducted as described (8). poorly controlled diabetic individuals (20–22). It is well Briefly, total splenocytes from the diabetic NOD mice were cocultured in vitro documented that severe periodontitis is the sixth most with 25Gy-irradiated syngeneic splenocytes as antigen-presenting cells and common complication among diabetic individuals (20– sonicated A. actinomycetemcomitans antigens (10 ␮g/ml) for 72 h, and 22). In addition, Lalla et al. (23) reported an increased al- subsequently, 25–30 ϫ 106 cells in PBS (per recipient) were used for tail vein injection into 4- to 6-week-old pre-diabetic NOD mice. Then, the recipients veolar bone loss in streptozotocin (STZ)-induced diabetic were immediately inoculated with A. actinomycetemcomitans orally two mice and attributed this to a higher expression of receptor times per week from weeks 1–3. All mice were killed between weeks 7 and 8 for advanced glycation end products via the advanced (typically 13–14 weeks old) and did not develop type 1 diabetes or hypergly- glycation end products signaling pathway. However, the
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