Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis

Abstract

Resveratrol is an antioxidant and anti-inflammatory polyphenol. Periodontitis is induced by oral pathogens, where a systemic inflammatory response accompanied by oxidative stress is the major event initiating disease. We investigated how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs). We also explored whether resveratrol protects rats against alveolar bone loss in an experimental periodontitis model. Periodontitis was induced around the first upper molar of the rats by applying ligature infused with LPS. Stimulating hGFs with 5μg/ml LPS augmented the expression of cyclooxygenase-2, matrix metalloproteinase (MMP)-2, MMP-9, and Toll-like receptor-4. LPS treatment also stimulated the production of reactive oxygen species (ROS) and the phosphorylation of several protein kinases in the cells. However, the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2 related factor 2 (Nrf2) was inhibited by the addition of LPS. Resveratrol treatment almost completely inhibited all of these changes in LPS-stimulated cells. Specifically, resveratrol alone augmented HO-1 induction via Nrf2-mediated signaling. Histological and micro-CT analyses revealed that administration of resveratrol (5mg/kg body weight) improved ligature/LPS-mediated alveolar bone loss in rats. Resveratrol also attenuated the production of inflammation-related proteins, the formation of osteoclasts, and the production of circulating ROS in periodontitis rats. Furthermore, resveratrol suppressed LPS-mediated decreases in HO-1 and Nrf2 levels in the inflamed periodontal tissues. Collectively, our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems.

Statement of significance: The aims of this study were to investigate how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs) and protects rats against alveolar bone disruption in an experimental periodontitis model. Our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems. On the basis of our experiment studies, we proposed that resveratrol could be used as novel bioactive materials or therapeutic drug for the treatment of periodontitis or other inflammatory bone diseases like osteoporosis, arthritis etc. Furthermore, it could be also used for the modification or coating of implant materials as an antiinflammatory molecules which will help to accelerate bone formation. There are a few of reports suggesting antioxidant and anti-inflammatory potentials of resveratrol. However, our results highlight the cellular mechanisms by which resveratrol inhibits LPS-mediated cellular damages using human-originated gingival fibroblasts and also support the potential of resveratrol to suppress periodontitis-mediated tissue damages. We believe that the present findings might improve a clinical approach of using of resveratrol on human, although further detailed experiments will be needed.

Keywords: HO-1; Lipopolysaccharide; Nrf2; Periodontitis; Resveratrol.