Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice
Evanthia Lalla, … , David M. Stern, Ann Marie Schmidt
Evanthia Lalla, … , David M. Stern, Ann Marie Schmidt
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1117-1124. https://doi.org/10.1172/JCI8942.
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Article

Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice

Abstract

Diabetes is associated with increased prevalence, severity, and progression of periodontal disease. To test the hypothesis that activation of RAGE (Receptor for Advanced Glycation End products) contributes to the pathogenesis of diabetes-associated periodontitis, we treated diabetic mice, infected with the human periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE is the extracellular domain of the receptor, which binds ligand and blocks interaction with, and activation of, cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted decreased generation of the proinflammatory cytokines TNF-α and IL-6 in gingival tissue, as well as decreased levels of matrix metalloproteinases. Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the observed suppression in alveolar bone loss. These findings link RAGE and exaggerated inflammatory responses to the pathogenesis of destructive periodontal disease in diabetes.

Authors

Evanthia Lalla, Ira B. Lamster, Michael Feit, Linda Huang, Alexandra Spessot, Wu Qu, Thomas Kislinger, Yan Lu, David M. Stern, Ann Marie Schmidt

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Administration of murine sRAGE results in dose-dependent suppression of ...
Administration of murine sRAGE results in dose-dependent suppression of alveolar bone loss in diabetic mice. (a) Alveolar bone loss. Male C57BL/6J mice were rendered diabetic with streptozotocin or treated with vehicle, citrate buffer alone. One month after documentation of diabetes or control state, all mice were inoculated with P. gingivalis, strain 381, as described in Methods. Immediately after inoculation, diabetic animals (filled bars) were treated with either MSA, 100 μg/day (n = 11), or sRAGE, 100 μg/day (n = 5), sRAGE, 50 μg/day (n = 13), sRAGE, 35 μg/day (n = 12), sRAGE, 25 μg/day (n = 11), sRAGE, 12 μg/day (n = 13), or sRAGE, 3.5 μg/day (n = 12) for 2 months. Similarly, non-diabetic mice (hatched bar) were treated with MSA, 100 μg/day (n = 12). Upon sacrifice, defleshed mandibles were assessed for extent of alveolar bone loss by morphometric analysis. Results are reported as mean arbitrary pixels per condition ± SE. In these studies, 12,210 pixels = 1 mm2. Statistical analyses are as follows: diabetes/MSA vs. non-diabetes/MSA, P = 0.009; diabetes/MSA vs.: sRAGE 25, 35, or 50 μg/day, P < 0.00001; sRAGE 100 μg/day, P < 0.0002; sRAGE, 3.5 μg/day, P = 0.28; and vs. sRAGE, 12 μg/day, P = 0.20. AStatistically significant differences compared with diabetes/MSA. (b–d). Representative photographs of mandibles. The lingual surfaces of posterior teeth are shown in defleshed half mandibles obtained from a non-diabetic mouse treated with MSA (b) and diabetic mice treated with MSA (c) or sRAGE(+) (d). The outlined areas between the CEJ and BC were computer analyzed and measured to evaluate differences in alveolar bone loss between groups. (e) Measurement of glycosylated hemoglobin. At the time of sacrifice, lysates of red blood cells were prepared as described and percent of glycosylated hemoglobin determined. The mean ± SE is reported. Statistical analyses are as follows: non-diabetes/MSA vs. diabetes/MSA, P = 0.005; diabetes/MSA vs. diabetes/sRAGE(+), P = 0.5; and diabetes/sRAGE(+) vs. non-diabetes/MSA, P = 0.005. AStatistically significant differences compared with diabetes/MSA or diabetes/sRAGE (+).