Rheumatoid Arthritis: Schmidt AM

Moser B, Hudson BI, Schmidt AM. · Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA. · Arthritis Res Ther. · Pubmed #15987496 links to  free full text

Abstract: The receptor for advanced glycation endproducts (RAGE) interacts with distinct ligand families linked to the inflammatory response. Studies in animal models suggest that RAGE is upregulated in the inflamed joint and that blockade of the receptor, using a ligand decoy soluble form of RAGE (sRAGE), attenuates joint inflammation and expression of inflammatory and tissue-destructive mediators. In this issue of Arthritis Research & Therapy, Rille Pullerits and colleagues reported that plasma levels of sRAGE were reduced in subjects with rheumatoid arthritis compared with healthy controls or subjects with non-inflammatory joint disease. These findings suggest the possibility that levels of sRAGE might be a biomarker of inflammation. Not resolved by these studies, however, is the intriguing possibility that endogenously higher levels of sRAGE might be linked to a lower incidence of arthritis or to the extent of inflammation. Nevertheless, although 'cause or effect' relationships may not be established in this report, fascinating insights into RAGE, inflammation and human arthritis emerge from these studies.

Hofmann MA, Drury S, Hudson BI, Gleason MR, Qu W, Lu Y, Lalla E, Chitnis S, Monteiro J, Stickland MH, Bucciarelli LG, Moser B, Moxley G, Itescu S, Grant PJ, Gregersen PK, Stern DM, Schmidt AM. · College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Genes Immun. · Pubmed #12070776 links to  free full text

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.

Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R. · CNR Institute of Clinical Physiology, Pisa, Italy. · Circulation. · Pubmed #11854121 links to  free full text

Abstract: BACKGROUND: The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation. METHODS AND RESULTS: AGEs, RAGE, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin are expressed in an overlapping manner in human inflamed rheumatoid synovia, especially within the endothelium. In primary cultures of human saphenous vein endothelial cells, engagement of RAGE by heterogeneous AGEs or Nepsilon(carboxymethyl)lysine-modified adducts enhanced levels of mRNA and antigen for vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. AGEs increased adhesion of polymorphonuclear leukocytes to stimulated endothelial cells in a manner reduced on blockade of RAGE. CONCLUSIONS: AGEs, through RAGE, may prime proinflammatory mechanisms in endothelial cells, thereby amplifying proinflammatory mechanisms in atherogenesis and chronic inflammatory disorders.