Accelerated Alveolar Bone Loss in Diabetic Mice Over-expressing Monocyte RAGE

We have previously reported that pharmacologic blockade of the Receptor for Advanced Glycation Endproducts (RAGE) in diabetic C57BL/6 mice infected with Porphyromonas gingivalis decreased alveolar bone loss in a dose-dependent manner. Objectives: We initiated new studies to further investigate the role of RAGE in diabetes-associated periodontitis, assess whether RAGE blockade therapy may have an adverse impact on the innate immune response to invading bacteria, and, thus, explore the efficacy and safety of such a therapeutic strategy in diabetes. Methods: We prepared transgenic mice over-expressing full-length functional RAGE selectively in cells of mononuclear phagocyte lineage driven by the macrophage scavenger receptor (MSR) promoter (C57BL/6 background). Hemizygous MSR RAGE transgenic mice were rendered diabetic with streptozotocin and subjected to oral infection with P. gingivalis one month after induction of diabetes. Non-diabetic transgenic and diabetic littermate wild type animals were also infected according to the same protocol and were used as controls. Mice in all groups were sacrificed three months after bacterial inoculation. Mandibles were dissected, defleshed, and photographed under a microscope. Slides were scanned and alveolar bone loss was assessed and compared between groups. Results: Upon induction of diabetes and P. gingivalis infection, transgenic mice (n=7) displayed dramatically increased alveolar bone loss compared to non-transgenic littermates (n=13) (8,010±608 vs 4,582±434 pixels, respectively; p<0.001). The contribution of diabetes on the acceleration of bone destruction was also evident, as alveolar bone loss was significantly higher in diabetic (n=7) vs non-diabetic (n =14) transgenic animals (8,010±608 vs 5,822±663, respectively; p<0.001). Conclusion: These findings confirm that activation of mononuclear phagocyte RAGE accelerates periodontal inflammation and alveolar bone destruction, and suggest that blockade of the receptor in diabetes is an effective and safe therapeutic strategy, without adverse impact on the innate immune response. Supported by USPHS HL 60901.