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Abstract Number: 0514

Extracellular Sulfatase-2 Mediates TNF-α Inflammatory Signaling in Human Rheumatoid Arthritis Synovial Fibroblasts

Ruby Siegel1, Anil singh1, Judy Vinh1, H. Mark Kenney2, Edward Schwarz3, David Fox4, Sadik Khuder5 and Salah-uddin Ahmed1, 1Washington State University, Spokane, WA, 2University of Rochester Medical Center, Rochester, NY, 3University of Rochester, Rochester, NY, 4Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI, 5Department of Medicine and Public Health, University of Toledo,, Toledo, OH

Meeting: ACR Convergence 2021

Keywords: Adhesion, Adhesion molecules, chemokines, Fibroblasts, Synovial, rheumatoid arthritis, Tumor necrosis factor (TNF)

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Session Information

Date: Sunday, November 7, 2021

Session Title: Cytokines & Cell Trafficking Poster (0508–0516)

Session Type: Poster Session B

Session Time: 8:30AM-10:30AM

Background/Purpose: TNF-α drives RA synovial fibroblast (RASF)-mediated hyperplasia and joint tissue destruction. Extracellular sulfatase-2 (Sulf-2) influences receptor/ligand binding and subsequent signaling of chemokines, cytokines, and growth factors, however, the potential role of Sulf-2 in TNF-α signaling has remained unexplored. Our study compared Sulf-2 expression in synovial tissues and serum from hTNFtg mice and human RA patients vs. non-diseased controls and determined effects of Sulf-2 on TNF-α signaling and inflammation in human RASFs.

Methods: Sulf-2 expression was measured in human non-diseased vs. RA synovial tissues (NLSTs vs. RASTs) by qRT-PCR and Western blotting. Sulf-2 expression in wild-type C57BL/6 vs. hTNFtg mouse ankle sections was compared by fluorescence IHC. Soluble Sulf-2 in mouse and human serum was measured by ELISA. Global effects of Sulf-2 gene knockdown by siRNA on TNF-α-induced gene expression were studied using an RNA sequencing (RNA-seq) array. Differentially expressed genes (DEGs) were analyzed using edgeR package of R software. Selected gene targets were validated by qRT-PCR and Western blotting/ELISA. TNF-α signaling pathways affected by Sulf-2 knockdown were analyzed.

Results: Sulf-2 mRNA was 3-fold higher (n=6 each; p< 0.001) and protein 5-fold higher (n=5 each; p< 0.01) in RAST vs. NLST. Soluble Sulf-2 in human serum was ~2-fold higher in RA (n=48) over non-diseased (NL, n=50; p< 0.001). Sulf-2 expression was elevated in the inflamed synovium of hTNFtg mice over wild-type (n=3 each). Soluble Sulf-2 was elevated ~20% in hTNFtg male mice (n=3, n.s.) and 2-fold in females (n=3, p< 0.05) over wild-type. In the RNA-seq array of TNF-α-activated RASFs, Sulf-2 siRNA modulated ~2,500 DEG vs. NC siRNA (FDR< 0.05). Gene ontology showed Sulf-2 significantly altered expression of genes in the canonical pathway role of macrophages, fibroblasts and endothelial cells in RA. qRT-PCR confirmed that Sulf-2 knockdown reduced TNF-α-induced ICAM1 (-58%), VCAM1 (-50%), CAD11 (-45%), PDPN (-34%), CCL5 (-55%), CX3CL1 (-59%), CXCL10 (-65%), CXCL11 (-63%) compared to NC siRNA (n=4-6, p< 0.01). Signaling studies identified PKC-δ as a key intermediate in TNF-α induced adhesion proteins. Sulf-2 knockdown suppressed TNF-α-induced p-PKC-δ (Thr505)(-52%) and p-JNK(Thr183/Tyr185)(-36%)(n=6; p< 0.05) and nuclear translocation of inflammatory transcription factors including NFkB p65 and c-Rel.

Conclusion: Our results provide novel evidence of the role of Sulf-2 in TNF-α activated signaling pathways in human RASFs. Further studies may decipher the therapeutic value of targeting Sulf-2 in the treatment of RA.


Disclosures: R. Siegel, None; A. singh, None; J. Vinh, None; H. Kenney, None; E. Schwarz, Janssen, Johnson & Johnson, 12, Anti-TNF and placebo antibodies were a gift from Janssen, J&J; D. Fox, None; S. Khuder, None; S. Ahmed, None.

To cite this abstract in AMA style:

Siegel R, singh A, Vinh J, Kenney H, Schwarz E, Fox D, Khuder S, Ahmed S. Extracellular Sulfatase-2 Mediates TNF-α Inflammatory Signaling in Human Rheumatoid Arthritis Synovial Fibroblasts [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/extracellular-sulfatase-2-mediates-tnf-%ce%b1-inflammatory-signaling-in-human-rheumatoid-arthritis-synovial-fibroblasts/. Accessed January 27, 2023.
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