Transthyretin and Receptor for Advanced Glycation End Product's Differential Levels Associated with the Pathogenesis of Rheumatoid Arthritis

• Published in: Journal of inflammation research Vol. 14; pp. 5581 - 5596
• Main Authors: Monu, Agnihotri, Prachi, Saquib, Mohd, Sarkar, Ashish, Chakraborty, Debolina, Kumar, Uma, Biswas, Sagarika
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2021; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: advanced glycation end products (ages); Alzheimer's disease; Antibodies; Apolipoproteins; differential proteins (dps); Enzyme-linked immunosorbent assay; Ethylenediaminetetraacetic acid; Fibroblasts; Gel electrophoresis; Gene expression; Genes; Glucose; Glycosylation; IL-1β; Inflammatory diseases; Influenza; Interleukin 6; Joint diseases; Mass spectrometry; Mass spectroscopy; NF-κB protein; Original Research; Osteoarthritis; Pathogenesis; Peptides; Plasma; post-translational modifications (ptm); Proteins; receptors for advanced glycation end products (rage); Rheumatic diseases; Rheumatism; Rheumatoid arthritis; rheumatoid arthritis (ra); Rheumatoid factor; Rheumatology; Scientific imaging; Software; Synoviocytes; Systemic lupus erythematosus; Transthyretin; transthyretin (ttr); Tumor necrosis factor-α; India; United States > US; differential proteins; post-translational modifications; receptor for advanced glycation end products; advanced glycation end products; rheumatoid arthritis; transthyretin
• ISSN: 1178-7031; 1178-7031
• DOI: 10.2147/JIR.S327736

Rheumatoid arthritis (RA) is a chronic autoimmune, inflammatory joint disease. The identification of multifaceted etiological changes at the protein level in RA remains an important need. We aimed to identify differential proteins (DPs) and gene profiles to uncover inflammatory indicators and their association to RA pathogenesis. 2-DE and SWATH-MS were used to identify DPs in RA and healthy control plasma. Fluorescence phenylboronate gel electrophoresis (Flu-PAGE) with mass spectrometry was used for protein glycation in RA plasma. Disease specificity of identified DPs was confirmed by ELISA and Western blot analysis. The gene expressions of selected DPs were evaluated by qRT-PCR in PBMCs of RA, systemic lupus erythematosus (SLE), spondyloarthritis (SpA), and osteoarthritis (OA). The functional implication of glycated protein was determined by in- silico and validated by in vitro analysis in fibroblast-like synoviocytes. A total of 150 DPs (127 increased and 23 decreased) were identified by 2-DE and SWATH-MS analysis in RA plasma compared to healthy control (HC). Nine proteins were identified as glycated by Flu-PAGE LC-MS/MS. Transthyretin (TTR), serotransferrin, and apolipoprotein-A1 (Apo-A1) were found to be differential and glycated. ELISA and Western blot results revealed the disease-specific increased expression of TTR and RAGE in RA. The qRT-PCR results signify the aberrant gene expression of TTR and RAGE, found to be associated with RA when compared with SLE, SpA, and OA PBMCs. TTR-RAGE interactions were predicted by - and validated by analysis using RA-FLS. The increased levels of pro-inflammatory cytokines IL-6, IL-1β, TNF-α, and differently expressed TTR and RAGE were confirmed in fibroblast-like synoviocytes under inflammatory conditions. Our findings showed that the level of TTR was increased in RA plasma, along with an altered glycation rate. TTR and RAGE aberrant gene expression in PBMCs are the key events associated with RA, and TNF-α activates the NF-KB pathways and promote TTR and RAGE differential expressions that may have pathogenic/inflammatory significance.