RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

Abstract

The receptor for advanced glycation end products (RAGE)

How RAGE turns in rage

“…In the same study Hofman et al 4 reported that the genetic variant that correlates with the expression of the more active RAGE 82S receptor, confers increased susceptibility for the development of RA. However, the picture is more complicated as it seems due to the high degree of linkage disequilibrium within the MHC.…”

“…For those reasons it is specially noteworthy that in the same paper Hofmann et al 4 elegantly provide evidence for a functional difference between the naturally occuring RAGE protein variants, ie, the wild-type with a glycine at position 82 and the variant with a serine in that position. The studies revealed significant differences in (i) the Kd between RAGE 82G (Kdෂ122+/−31 nM) and RAGE 82S (Kdෂ77+/−21 nM) receptors, (ii) the EN-RAGE induced phosphorylation of MEK1/2 and p44/42 MAP kinases and NF-B induction (RAGE 82SϾG), and (iii) EN-RAGE induced production of the pro-inflammatory cytokines TNF-␣ and IL-6, and the metalloproteinases (MMP) 3, 9 and 13 (RAGE 82SϾG).…”

“…4 Previous studies already suggested a pivotal role of RAGE activation in the pathogenesis of diabetic vascular disease and Alzheimer. 5,6 RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors that binds advanced glycation end products (AGE)-the products of nonenzymatic glycoxidation of protein/lipids-and amyloid-␤ peptide, a cleavage product of the ␤-amyloid precursor protein.…”

“…In this issue Hofmann et al 4 provide evidence for a role of the gene encoding the receptor for advanced glycation end products (RAGE), implicated in the amplification of immune responses, as good candidate for a genetic factor that contributes to RA. 4 Previous studies already suggested a pivotal role of RAGE activation in the pathogenesis of diabetic vascular disease and Alzheimer.…”

“…11 It is in this context that the authors performed studies in a collagen-induced murine arthritis model, which demonstrated that blockade of RAGE suppressed clinical, molecular and histological evidence of arthritis, thereby supporting a functional role for RAGE in arthritis. 4 These findings made the RAGE gene an attractive candidate to study for the existence of allelic variations that might be important in the pathogenesis of inflammatory disease. The RAGE gene is located in the MHC locus on chromosome 6p21.3, which contains multiple genes involved in inflammatory and immune responses and is known for its multifold disease associations.…”