Exenatide ameliorates inflammatory response in human rheumatoid arthritis fibroblast‐like synoviocytes

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology characterized by degradation of cartilage and bone, accompanied by unimpeded proliferation of synoviocytes of altered phenotype. In the present study, we investigated the involvement of the glucagon‐like peptide 1 (GLP‐1) receptor on human fibroblast‐like synoviocytes (FLS) in the pathogenesis of RA using the selective GLP‐1 agonist exenatide, a licensed drug used for the treatment of type 2 diabetes. Our results indicate that exenatide may play a role in regulating tumor necrosis factor‐α‐induced mitochondrial dysfunction by increasing mitochondrial membrane potential, oxidative stress by reducing the production of reactive oxygen species, the expression of NADPH oxidase 4, expression of matrix metalloproteinase (MMP)‐3 and MMP‐13, release of proinflammatory cytokines including interleukin‐1β (IL‐1β), IL‐6, monocyte chemoattractant protein‐1, and high‐mobility group protein 1, as well as activation of the p38/nuclear factor of κ light polypeptide gene enhancer in B‐cells inhibitor, α/nuclear factor κB signaling pathway in primary human RA FLS. These positive results indicate that exenatide may have potential as a therapeutic agent for the treatment and prevention of RA. © 2019 IUBMB Life, 9999(9999):1–9, 2019

Glucagon-Like Peptide 1 Receptor Agonists in Patients With Inflammatory Arthritis or Psoriasis

“…Of the 5 RA publications, 3 were basic science experiments 28,29,32 and 2 were clinical conference abstracts (1 case report and 1 longitudinal cohort) 30,31 . There were 13 psoriasis publications: 2 basic science experiments (including 1 mouse model), 33,41 2 studies with a basic science and clinical component (ie, case report or cross-sectional study), 36,45 4 case reports, 35,39,43,44 3 uncontrolled longitudinal cohort studies, 34,37,40 and 2 RCTs (1 placebo-controlled and 1 with an active comparator without blinding) 38,42 …”

“…In RA, 3 basic science experiments evaluated the effect of GLP-1 receptor agonists on human fibroblast-like synoviocytes (FLSs) stimulated by either IL-1β or TNF-α 28,29,32 . In all 3 studies, there was a dose-dependent statistically significant reduction in oxidative stress, in activation of key proinflammatory pathways (such as NF-κB), in mitochondrial dysfunction, and in expression of proinflammatory cytokines (including TNF-α and IL-6), and collagen degradative enzymes (eg, MMP-3 and MMP-13) when stimulated FLSs were treated with lixisenatide, exenatide, or dulaglutide.…”

“…In all 3 studies, there was a dose-dependent statistically significant reduction in oxidative stress, in activation of key proinflammatory pathways (such as NF-κB), in mitochondrial dysfunction, and in expression of proinflammatory cytokines (including TNF-α and IL-6), and collagen degradative enzymes (eg, MMP-3 and MMP-13) when stimulated FLSs were treated with lixisenatide, exenatide, or dulaglutide. Greater improvements were observed with higher doses of GLP-1 receptor agonists: certain cytokines, enzymes, reactive oxygen species, and signaling molecules improved to near normal levels with higher dose treatment 28,29,32 . Although various mechanisms were discussed accounting for the anti-inflammatory effects of GLP-1 receptor agonists, inhibition of one common signaling pathway was highlighted by the 3 studies: NF-κB.…”

“…Although various mechanisms were discussed accounting for the anti-inflammatory effects of GLP-1 receptor agonists, inhibition of one common signaling pathway was highlighted by the 3 studies: NF-κB. GLP-1 receptor agonists have been found to prevent phosphorylation (and subsequent degradation) of IκBα, a key inhibitory protein that normally prevents nuclear translocation of NF-κB transcription factors responsible for downstream proinflammatory cytokine production 29,32,47 …”

Insulin Signaling in Arthritis

“…Exenatide treatment significantly reduced expression of IL-1b, IL-6, MMP-3, MMP-13 and MCP-1. Moreover, by preventing IkBa degradation, the treatment inhibited activation of the p38/ MAPK and NF-kB pathways (143).…”