G(−) Anaerobes–Reactive CD4+ T-Cells Trigger RANKL-Mediated Enhanced Alveolar Bone Loss in Diabetic NOD Mice

Abstract

Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell-mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(؊) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans-reactive CD4 ؉ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor B ligand (RANKL) expression. When diabetic mice are treated with the RANKL antagonist osteoprotegerin (OPG), there is a significant reversal of alveolar bone loss, as well as reduced RANKL expression in A. actinomycetemcomitans-reactive CD4 ؉ T-cells. This study clearly describes the impact of autoimmunity to anaerobic infection in an experimental periodontitis model of type 1 diabetes. Thus, microorganism-reactive CD4 ؉ T-cells and the RANKL-OPG axis provide the molecular basis of the advanced periodontal breakdown in diabetes and, therefore, OPG may hold therapeutic potential for treating bone loss in diabetic subjects at high risk. Diabetes

Chronic Hyperglycemia Predisposes to Exaggerated Inflammatory Response and Leukocyte Dysfunction in Akita Mice

“…Similarly MIP-1␣, the chemokine most enhanced in Akita mice, potently enhances osteoclast formation (51), thus raising the possibility that MIP-1␣ directly enhances alveolar bone loss in Akita mice. The Akita cytokine pattern is also consistent with increased T cell recruitment, and receptor activator NF-B ligand-mediated activation of osteoclast precursors by T cells has been shown to contribute to alveolar bone loss (16).…”

“…Hyperglycemia plays an important role because both insulin-dependent and non-insulin-dependent diabetes patients are affected, and HbA1c levels inversely correlate with periodontal health (14). Several aspects of diabetic damage to the periodontium have been explored, such as the role of AGE (15), T cell activation (16), and polymorphonuclear neutrophil (PMN)-mediated free radical damage (14). PMN are of particular interest because both acute and chronic PMN deficiency (neutropenia) cause severe oral ulcers and periodontal disease, indicating that PMN are essential in oral mucosal defense (17,18).…”

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

“…A number of studies focusing on osteoclastogenesis-related factors have reported elevated levels of RANKL in diabetes-associated periodontal tissues (Mahamed et al 2005, Duarte et al 2007b, Lappin et al 2009). Studies in gingival crevicular fluid demonstrated that RANKL and the RANKL to OPG ratio are higher in poorly controlled diabetic patients with periodontitis compared to well-controlled or non-diabetic subjects with similar periodontal status (Santos et al 2010a, Vieira Ribeiro et al 2011.…”

Diabetic complications and dysregulated innate immunity

“…They also showed significantly higher receptor activator of nuclear factor kappaB ligand (RANKL) expression and when treated with osteoprotegerin (OPG), diabetic mice showed a significant reversal of alveolar bone loss, as well as reduced RANKL expression. (78). Mechanisms by which diabetes may impact aspects of the innate immune response associated with periodontal tissue loss such as increased cytokine and superoxide production are discussed below.…”