Receptor for advanced glycation end product (RAGE) upregulation in human gingival fibroblasts incubated with nornicotine

J Periodontol. 2005 Jul;76(7):1171-4. doi: 10.1902/jop.2005.76.7.1171.


Background: Clinical and epidemiological data strongly support a link between smoking and periodontal disease. The mechanism by which smoking contributes to the destruction of periodontal tissue is not clear and cannot be attributed solely to the vasoconstrictive effects of nicotine. Our hypothesis is that nornicotine, a metabolite of nicotine, upregulates the expression of the receptor for the advanced glycation end products (RAGE) in the gingiva of smokers and triggers the proinflammatory effects of AGE by stimulating the secretion of cytokines and reactive oxygen species which directly cause destruction of the periodontal apparatus.

Methods: Human gingival cells grown in tissue culture were exposed to 1 microM nornicotine for 72 hours. Following the nornicotine pretreatment, some of the cells were also treated with AGE that was generated with nornicotine for 48 hours and another group was continued on nornicotine only for 48 hours. Control cells that were not exposed to either nornicotine or AGE were also cultured. The cells were harvested and RNA was extracted for reverse transcription-polymerase chain reaction (RT-PCR) and RAGE mRNA was amplified.

Results: The nornicotine-treated cells increased their expression of RAGE by approximately 4-fold (P <0.05, Student t test). These data suggest that nornicotine, a byproduct of cigarette smoke, can induce RAGE expression in gingival tissues. Therefore, our data support the hypothesis that RAGE potentially plays a significant role in the progression of periodontal disease exacerbated by smoking.

Conclusion: Nornicotine, AGE, and upregulation of RAGE may be involved in the pathogenesis of periodontal disease associated with smoking.

MeSH terms

  • Cell Line
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Gingiva / cytology
  • Gingiva / drug effects*
  • Gingiva / metabolism
  • Glycation End Products, Advanced / biosynthesis*
  • Glycation End Products, Advanced / physiology
  • Humans
  • Inflammation Mediators / metabolism
  • Nicotine / analogs & derivatives*
  • Nicotine / pharmacology
  • Periodontal Diseases / etiology
  • RNA, Messenger / biosynthesis
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Smoking / adverse effects
  • Up-Regulation


  • Glycation End Products, Advanced
  • Inflammation Mediators
  • RNA, Messenger
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Nicotine
  • nornicotine