ArticleArthritis research & therapy2024
Diminished expression of the ubiquitin-proteasome system in early treatment-naïve patients with rheumatoid arthritis and concomitant type 2 diabetes may be linked to IL-1 pathway hyper-activity; results from PEAC cohort.
Article in Arthritis research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Role of the Proteasome System in Shaping Cellular Immunological Characteristics and Its Impact in Modulating the Pathogenesis of Immune-Related Diseases.Cells, tissues, organs · 2026Review
- Synovial infiltrating immune cell heterogeneity associated with synovitis severity and systemic disease activity in rheumatoid arthritis: a cross-sectional study.Clinical rheumatology · 2025Article
- Article
- Proteasome-driven modulation of immune and oxidative pathways during scorpion envenomation pathogenesis.The journal of venomous animals and toxins including tropical diseases · 2025Article
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Abstract
objectiveBased on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin-proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs).
methodsThe synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot.
resultsSynovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin-proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM).
conclusionsA different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin-proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.
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