Advanced oxidation protein products induce inflammatory responses and invasive behaviour in fibroblast-like synoviocytes via the RAGE-NF-κB pathway

Abstract

Aims Rheumatoid arthritis (RA), which mainly results from fibroblast-like synoviocyte (FLS) dysfunction, is related to oxidative stress. Advanced oxidation protein products (AOPPs), which are proinflammatory mediators and a novel biomarker of oxidative stress, have been observed to accumulate significantly in the serum of RA patients. Here, we present the first investigation of the effects of AOPPs on RA-FLSs and the signalling pathway involved in AOPP-induced inflammatory responses and invasive behaviour. Methods We used different concentrations of AOPPs (50 to 200 µg/ml) to treat RA-FLSs. Cell migration and invasion and the expression levels of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and MMP-13 were investigated. Western blot and immunofluorescence were used to analyze nuclear factor-κB (NF-κB) activation. Results AOPPs promoted RA-FLS migration and invasion in vitro and significantly induced the messenger RNA (mRNA) and protein expression of TNF-α, IL-6, MMP-3, and MMP-13 in dose- and time-dependent manners. Moreover, AOPPs markedly activated the phosphorylation of nuclear factor-κB (NF-κB) p65 protein, which triggered inhibitory kappa B-alpha (IκBα) degradation, NF-κB p65 protein phosphorylation, and NF-κB p65 translocation into the nucleus. Furthermore, treatment with a neutralizing antibody specific to receptor for advanced glycation end products (RAGE) significantly suppressed aggressive behaviour and inflammation, decreased TNF-α, IL-6, MMP-3, and MMP-13 expression, and blocked AOPP-induced NF-κB pathway activation. Conclusion The results indicate that AOPPs can enhance aggressive behaviour and the inflammatory response in RA-FLSs via the RAGE–NF-κB pathway. These results present AOPPs as a new class of potentially important mediators of progressive disease in RA patients. Cite this article: Bone Joint Res 2021;10(4):259–268.

Immunomodulatory role of T helper cells in rheumatoid arthritis

“…20 Loss of normal synovial protection alters the proteinbinding characteristics of the cartilage surface, promoting adhesion and invasion by fibroblast-like synoviocytes (FLSs), and the proliferation of FLSs is the main cause of invasive pannus formation in RA pathogenesis. 21,22 FLSs synthesize matrix metalloproteinases (MMPs), particularly MMP-1, -3, -8, -13, -14, and -16, promoting breakdown of the type II collagen network, a process that alters glycosaminoglycan content and water retention, directly leading to biomechanical dysfunction. 23 A recent study found that overexpressed microRNA (miR)-486 accelerates the reduction of aggregative proteoglycan by upregulating the expression of A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) and MMP-13, resulting in more decomposition of chondrocytes.…”

Significance of Serum Oxidative and Antioxidative Status in Congenital Central Hypoventilation Syndrome (CCHS) Patients

“…AOPPs resulting from myeloperoxidase activation and hypochlorous acid production during inflammation are capable of binding to pattern recognition receptors (PRRs) whose downstream effects result in the activation of OS and inflammatory pathways including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor-κB (NF-κB) activation [ 30 ]. Among the PPRs activated by AOPPs, the receptor of advanced glycation end-products (RAGE) is implicated in diverse chronic inflammatory states and has been linked to vascular lesions in diabetes, renal diseases, and atherosclerosis [ 31 , 32 ]; AOPPs have been also found increased in patients with inflammatory conditions such as Crohn’s disease [ 4 ], rheumatoid arthritis [ 33 ], and obstructive sleep apnea syndrome [ 34 ].…”

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