Receptor for AGE (RAGE): Weaving tangled webs within the inflammatory response

Division of Surgical Science, Department of Surgery, Columbia University Medical Center, 630 West 168th Street, P&S 17-501, New York, NY 10032, USA.
Current Molecular Medicine (Impact Factor: 3.61). 01/2008; 7(8):743-51. DOI: 10.2174/156652407783220714
Source: PubMed

ABSTRACT The family of RAGE ligands, including Advanced Glycation Endproducts (AGEs), S100/calgranulins, High Mobility Group Box-1 (HMGB1) and amyloid beta peptide (Abeta) and beta-sheet fibrils are highly enriched in immune and inflammatory foci. In parallel, upregulation of Receptor for AGE (RAGE) is noted in diverse forms of inflammation and autoimmunity, based on experiments examining human tissues as well as animal models. Indeed, prior to the demonstration that S100/calgranulins were signal transduction ligands of RAGE, these molecules were considered "biomarkers" of disease and disease activity in disorders such as colitis and arthritis. Premiere roles for RAGE in advancing cellular migration implicate this receptor in targeting immune cells to vulnerable foci. Once engaged, ligand-RAGE interaction in inflammatory and vascular cells amplifies upregulation of inflammatory cytokines, adhesion molecules and matrix metalloproteinases (MMPs). Discerning the primal versus chronic injury-provoking roles for this ligand-receptor interaction is a challenge in delineating the functions of the ligand/RAGE axis. As RAGE is expressed by many of the key cell types linked integrally to the immune response, we propose that the sites and time course of ligand-RAGE stimulation determine the phenotype produced by this axis. Ultimately, drawing the fine line between antagonism versus stimulation of the receptor in health and disease will depend on the full characterization of RAGE in repair versus injury.

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    ABSTRACT: The receptor for advanced glycation end products (RAGE), a member of immunoglobulin superfamily, has been proved to stimulate survival, growth, and metastatic spread of cancers cells. Evidence suggested that the 82G/S, -374T/A, and -429T/C polymorphisms in RAGE promoter region might affect the risk of cancer; however, data from epidemiological studies showed conflicting results that remain to be further clarified. This meta-analysis was performed to derive a more precise estimation of 82G/S, -374T/A, and -429T/C polymorphisms and risk of cancer. A comprehensive electronic search was conducted for articles published up until December 2, 2014, in Medline (PubMed), Embase, the Cochrane Library and Google Scholar. A total of 12 case-control articles were included in this meta-analysis, providing 3,374 cases and 3,757 controls for 82G/S, 2,936 cases and 3,338 controls for -374T/A, and 2,882 cases and 3,279 controls for -429T/C specifically. The pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to evaluate the associations with risk of cancer. Overall, we observed significantly increased risk of cancer in relation to 82G/S (A vs. G: OR 1.321, 95 % CI 1.164-1.499, P het 0.028; AA vs. GG: OR 1.823, 95 % CI 1.541-2.157, P het < 0.001; AG vs. GG: OR 1.399, 95 % CI 1.120-1.746, P het 0.002; GA+AA vs. GG: OR 1.470, 95 % CI 1.187-1.821, P het 0.002; AA vs. GG+AG: OR 1.416, 95 % CI 1.158-1.732, P het 0.107) and reduced risk of cancer in relation to -374T/A (AA vs. TT: OR 0.818, 95 % CI 0.686-0.976, P het 0.025; A vs. T: OR 0.908, 95 % CI 0.840-0.981, P het 0.014). In subgroup analysis for 82G/S, a significantly elevated cancer risk was indicated in the population of Asian and patients with lung cancer, and for -374T/A, reduced risk was indicated in population of Caucasian and patients with lung cancer and breast cancer. But no significant association was observed between -429T/C and risk of cancer. Thus, this meta-analysis revealed that 82G/S polymorphism is associated with a significantly increased risk of cancer, while -374T/A polymorphism is associated with a reduced risk of cancers.
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    ABSTRACT: Oral squamous cell carcinoma is a common neoplasm that is known to be causally associated with genetic factors and environmental carcinogens. The receptor for advanced glycosylation endproducts (RAGE) is a transmembrane protein of the immunoglobulin superfamily with broad specificity for multiple ligands, and it has been shown to play vital roles in several pathophysiologic processes, including diabetes, Alzheimer disease, renal disease, cardiovascular disease, and cancer. The present study aimed to assess the influences of RAGE gene polymorphisms, combined with environmental carcinogens on the predisposition to oral tumorigenesis. Five polymorphisms of the RAGE gene-including -374T>A (rs1800624), -429T>C (rs1800625), 1704G>T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (-407 to -345)-were examined from 592 controls and 618 patients with oral cancer. We found that individuals carrying the polymorphic allele of rs1800625 are more susceptible to oral cancer (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.355 to 2.661; adjusted OR [AOR], 2.053; 95% CI, 1.269 to 3.345) after adjustment for age, sex, betel nut chewing, and tobacco consumption. Moreover, we observed a significant association of rs1800625 variants with late-stage tumors (stage III/IV, OR, 1.736; 95% CI, 1.126 to 2.677; AOR, 1.771; 95% CI, 1.101 to 2.851) and large-size tumors (>2 cm in the greatest dimension; OR, 1.644; 95% CI, 1.083 to 2.493; AOR, 1.728; 95% CI, 1.089 to 2.741). Based on behavioral exposure of environmental carcinogens, the presence of 4 RAGE single-nucleotide polymorphisms (SNPs), combined with betel quid chewing and/or tobacco use, greatly augmented the risk of oral cancer. In addition, carriers of particular haplotypes of the 4 RAGE SNPs examined are more prone to develop oral cancer. These results indicate an involvement of RAGE SNP rs1800625 in the development of oral squamous cell carcinoma and implicate the interaction between RAGE gene polymorphisms and environmental mutagens as a predisposing factor of oral carcinogenesis. © International & American Associations for Dental Research 2015.
    Journal of Dental Research 01/2015; DOI:10.1177/0022034514566215 · 4.14 Impact Factor
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    ABSTRACT: RAGE, receptor for advanced glycation endoproducts (AGE), has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE) demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA) partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.
    PLoS ONE 10/2014; 9(10):e108819. DOI:10.1371/journal.pone.0108819 · 3.53 Impact Factor