In a groundbreaking study published in Annals of the Rheumatic Diseases, researchers have uncovered a novel role of erythropoietin (EPO) in the progression of rheumatoid arthritis (RA), shedding light on its potential as a target for therapeutic intervention. EPO, traditionally known for its role in stimulating red blood cell production, was found to exacerbate RA by promoting desialylation—a biochemical process that influences cell migration and invasion—through the upregulation of neuraminidase 3 (NEU3).
The results revealed a marked increase in EPO levels in RA patients, which was positively correlated with the Disease Activity Score (DAS28). Further investigation using collagen-induced arthritis (CIA) mice models confirmed that EPO intervention significantly aggravated joint destruction. Transcriptome sequencing of EPO-treated fibroblast-like synoviocytes (FLS) identified NEU3 as a differentially expressed gene, with its expression being notably upregulated.
The transcription factor responsible for NEU3 expression was identified as signal transducer and activator of transcription 5 (STAT5), which was shown to be activated by the Janus kinase 2 (JAK2) pathway. This pathway, triggered by EPO binding to its receptor EPOR, ultimately leads to the enhanced expression of NEU3, resulting in increased desialylation. This process, in turn, promotes the migration and invasion abilities of FLS, contributing to the progression of RA. The findings were further validated through experiments using JAK2 and NEU3 inhibitors, which effectively mitigated the pro-inflammatory effects of EPO on RA. The study’s conclusions suggest that EPO acts as a proinflammatory factor in RA by upregulating NEU3 expression via the JAK2/STAT5 signaling pathway.
EPO, a key factor in stimulating erythrocyte production, primarily activates the JAK2/STAT5 pathway to regulate the proliferation, differentiation, and maturation of erythroid progenitor cells. Beyond its well-known role in hematopoiesis, recent studies have increasingly highlighted the extrahaematopoietic effects of EPO in non-blood-related tissues. In the context of rheumatoid arthritis (RA), it is noteworthy that approximately 64% of RA patients experience anemia, which is accompanied by a compensatory rise in serum EPO levels. A study by Birgegård et al. has also established a positive correlation between serum EPO concentrations in RA patients and the erythrocyte sedimentation rate (ESR), a key marker of inflammation. Another study by Nielsen et al. reported a positive correlation between serum EPO levels and both C-reactive protein and ESR in patients with RA.
This present study discovery opens new avenues for RA treatment, as targeting the EPO-NEU3 axis could potentially slow down or prevent the progression of the disease. The research highlights the importance of understanding the multifaceted roles of cytokines like EPO in chronic inflammatory diseases and paves the way for the development of novel therapeutic strategies aimed at improving the quality of life for RA patients.
References
- Wu G, Cao B, Zhai H, Liu B, Huang Y, Chen X et al. EPO promotes the progression of rheumatoid arthritis by inducing desialylation via increasing the expression of neuraminidase 3. Ann Rheum Dis. 2024 Apr 11;83(5):564-575.
- Birgegård G, Hällgren R, Caro J. Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritides: relationship to anaemia and the effect of anti-inflammatory treatment. Br J Haematol. 1987 Apr;65(4):479-83.
- Nielsen OJ, Andersen LS, Ludwigsen E, Bouchelouche P, Hansen TM, Birgens H et al. Anaemia of rheumatoid arthritis: serum erythropoietin concentrations and red cell distribution width in relation to iron status. Ann Rheum Dis. 1990 Jun;49(6):349-53.