RAGE and arthritis: The G82S polymorphism amplifies the inflammatory response

M. A. Hofmann, S. Drury, B. I. Hudson, M. R. Gleason, W. Qu, Y. Lu, E. Lalla, S. Chitnis, J. Monteiro, M. H. Stickland, L. G. Bucciarelli, B. Moser, G. Moxley, S. Itescu, P. J. Grant, P. K. Gregersen, D. M. Stern, A. M. Schmidt

Research output: Contribution to journalArticle

306 Scopus citations

Abstract

The receptor for advanced glycation end products (RAGE) and its proinflammatory S100/calgranulin ligands are enriched in joints of subjects with rheumatoid arthritis (RA) and amplify the immune/inflammatory response. In a model of inflammatory arthritis, blockade of RAGE in mice immunized and challenged with bovine type II collagen suppressed clinical and histologic evidence of arthritis, in parallel with diminished levels of TNF-alpha, IL-6, and matrix metalloproteinases (MMP) 3, 9 and 13 in affected tissues. Allelic variation within key domains of RAGE may influence these proinflammatory mechanisms, thereby predisposing individuals to heightened inflammatory responses. A polymorphism of the RAGE gene within the ligand-binding domain of the receptor has been identified, consisting of a glycine to serine change at position 82. Cells bearing the RAGE 82S allele displayed enhanced binding and cytokine/MMP generation following ligation by a prototypic S100/calgranulin compared with cells expressing the RAGE 82G allele. In human subjects, a case-control study demonstrated an increased prevalence of the 82S allele in patients with RA compared with control subjects. These data suggest that RAGE 82S upregulates the inflammatory response upon engagement of S100/calgranulins, and, thereby, may contribute to enhanced proinflammatory mechanisms in immune/inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)123-135
Number of pages13
JournalGenes and Immunity
Volume3
Issue number3
DOIs
StatePublished - May 1 2002
Externally publishedYes

Keywords

  • Inflammation
  • Joint
  • Polymorphism
  • Receptor
  • S100/calgranulin

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics

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    Hofmann, M. A., Drury, S., Hudson, B. I., Gleason, M. R., Qu, W., Lu, Y., Lalla, E., Chitnis, S., Monteiro, J., Stickland, M. H., Bucciarelli, L. G., Moser, B., Moxley, G., Itescu, S., Grant, P. J., Gregersen, P. K., Stern, D. M., & Schmidt, A. M. (2002). RAGE and arthritis: The G82S polymorphism amplifies the inflammatory response. Genes and Immunity, 3(3), 123-135. https://doi.org/10.1038/sj.gene.6363861