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 sRAGE to diabetic mice results in diminished levels of...
Administration of sRAGE to diabetic mice results in diminished levels of MMP protein and activity. (a, b) Immunoblotting. (a) MMP-9. Gingival tissue extracts were prepared as described and total protein (150 ng) was subjected to electrophoresis on Tris-glycine gels. The contents of the gels were transferred to nitrocellulose membranes, and immunoblotting was performed using mouse monoclonal anti-MMP 9 (2 μg/mL). Densitometry was performed using ImageQuant. Molecular weight markers (kDa) are indicated at the right of the immunoblot. In these experiments, intensity of the band obtained from gingival extract of non-diabetic MSA-treated animals was arbitrarily defined as 1. These experiments were performed 3 times with analogous results. (b) MMP-3. These experiments were performed as described in a; final concentration of anti-MMP-3 IgG was 1 μg/mL. (c) Zymography. At sacrifice, gingival extracts were prepared as described. Two hundred twenty nanograms of total protein per sample was subjected to chromatography onto gels containing gelatin (0.1%); bands representing MMP-2 are indicated. Densitometric analysis was performed and is demonstrated in the inset. Bands from non-diabetic mice treated with MSA were arbitrarily defined as 1. These experiments were performed 3 times with analogous results.