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Abstract Number: 0880

Investigating the SRPK-1-VEGF-A Alternative Splicing Pathway AsaTherapeutic Target in Arthritis

Charles Besidonne1, Andrew Benest1, Kim Chisholm1, Jonathan Morris2, Lucy Donaldson3, Jeanette Woolard4 and David Bates1, 1University of Nottingham, Nottingham, United Kingdom, 2University of New South Wales, New South Wales, New South Wales, Australia, 3Versus Arthritis UK, Nottingham, United Kingdom, 4University of Nottingham, Nottingham, England, United Kingdom

Meeting: ACR Convergence 2024

Keywords: Angiogenesis, Inflammation, Interleukins, Protein Kinase, Tumor necrosis factor (TNF)

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Session Information

Date: Sunday, November 17, 2024

Title: Cytokines & Cell Trafficking Poster

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Alternative pre-mRNA splicing of Vascular Endothelial Growth Factor-A (VEGF-A) produces pro-angiogenic (VEGF-Axxxa) or anti-angiogenic (VEGF-Axxxb) isoforms that contribute to angiogenesis in inflammatory arthritis. Isoform expression is regulated by post-translational modification of serine-arginine-rich splicing factor-1 (SRSF-1) by Serine Arginine Protein Kinase 1 (SRPK-1). Increased expression of the anti-angiogenic VEGF-A isoform (VEGF-Axxxb) could be a potential therapeutic target for inflammation and pain in inflammatory arthritis. We therefore tested the hypothesis that VEGF-A165b is expressed, and VEGF splicing is regulated in synovial fibroblasts in culture. 

Methods: Normal human fibroblast-like synoviocytes (HFLS) were stimulated with Tumour necrosis factor alpha(TNF-a) and interleukin-1 beta (IL-1b) and with an SRPK-1 inhibitor in-vitro. The effect of TNF-a and IL-1b on VEGF-A splice variant expression, with and without SRPK1 inhibition, was measured using RT-PCR and ELISA. Normal HFLS were fixed and immuno-stained for SRSF-1 and SRSF-2.  

Results: Treatment with TNF-a and IL-1b (20ng/ml) caused the early nuclear translocation of SRSF-1 after 2h. Treatment with IL-1b led to a switch in splicing to the pro-angiogenic VEGF-A165a isoform at mRNA level after 24h. Increased association of SRSF-1 and CLK-1 was observed within nuclear speckles, indicating that this splicing is regulated by an SRSF-1-CLK-1–SRSF-2 interaction. Co-incubation with the SRPK-1 Inhibitor decreased the association of SRSF-1 to nuclear speckles and reversed the early nuclear translocation of SRSF-1. 

Conclusion: Tumour necrosis factor- alpha and interleukin-1 beta regulate the alternative splicing pathway of VEGF-A in fibroblast-like synoviocytes via SRPK-1


Disclosures: C. Besidonne: None; A. Benest: None; K. Chisholm: None; J. Morris: None; L. Donaldson: None; J. Woolard: None; D. Bates: None.

To cite this abstract in AMA style:

Besidonne C, Benest A, Chisholm K, Morris J, Donaldson L, Woolard J, Bates D. Investigating the SRPK-1-VEGF-A Alternative Splicing Pathway AsaTherapeutic Target in Arthritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/investigating-the-srpk-1-vegf-a-alternative-splicing-pathway-asatherapeutic-target-in-arthritis/. Accessed .
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