Researchers Identify Key Protein Driving Inflammation in RA

The findings, produced over a 4-year period, indicate the protein sulfatase-2 (Sulf-2) may be a therapeutic target in rheumatoid arthritis (RA).

Researchers of a new study have identified a novel driver of inflammation in rheumatoid arthritis (RA). The findings, produced over a 4-year period, indicate the protein sulfatase-2 (Sulf-2) may be a therapeutic target in the condition, according to the authors whose findings appeared in Cellular & Molecular Immunology.

According to the group, their study is the first to characterize the role of extracellular sulfatases in tumor necrosis factor (TNF)-α signaling and RA synovial pathogenesis. Sulf-2, which regulates receptor–ligand binding and subsequent signaling by chemokines and growth factors, has been recognized as a novel therapeutic target in cancer. However, the role of Sulf-2 in inflammatory cytokine signaling has not been assessed to date, including in RA.

For patients with RA, TNF inhibitors are a mainstay of treatment, although patients may develop resistance to such treatments over time, and long-term use of the treatments is associated with a risk of serious infection, immunogenicity, and malignancy, creating a need for other drug targets. By identifying Sulf-2 in the role of inflammation, the researchers note that their findings have potential for improving treatment.

“TNF inhibitors have radically changed the treatment of patients with refractory RA, but they are expensive, immunosuppressive, and sometimes unsuitable for long-term use,” explained the researchers. “Existing RA therapies are directed at B cells, T cells, and cytokines. No existing medication for RA targets RA synovial fibroblasts[RASFs] despite a body of molecular and clinical evidence for their active role in RA pathogenesis. Our results suggest that targeting Sulf-2 as an adjunct therapeutic approach to limit TNF-α–induced synovial hyperplasia and tissue destruction may represent a unique opportunity to suppress synovial inflammation (but not systemic host defenses) and improve conventional RA therapy.”

Throughout their research, the researchers found that elevated levels of Sulf-2 in tissue samples were significantly associated with RA in both patients and in human TNF-α-transgenic mice compared with those without RA. Sulf-2 mRNA levels were 3-fold higher in human RA synovial tissues.

The group collected joint-lining cells of patients with RA for at least 2 years and not yet treated with biologics, removing Sulf-2 from some of them. After stimulating all cells with TNF-α, they observed that the cells without Sulf-2 showed a less prominent inflammatory response.

“Looking at sulfatases for their potential role in inflammation was an educated guess, but once we did we saw a very consistent pattern of increased sulfatase-2 expression throughout different tissues and samples we studied,” said study author Salah-uddin Ahmed, PhD, a professor in Washington State University’s College of Pharmacy and Pharmaceutical Sciences, in a press release. “This tells us that TNF-α relies on sulfatase-2 to drive inflammation, because as soon as we removed sulfatase-2, the inflammatory effects of TNF-α were markedly reduced.”

To assess the role of Sulf-2 in TNF-α­–stimulated RASFs, the researchers used a loss-of-function approach and RNA analysis, finding that Sulf-2 small interfering RNA modulated approximately 2500 genes compared with scrambled siRNA. A volcano plot showed a prominent reduction in various inflammatory genes compared with TNF-α­ alone.

Their analysis showed that in the absence of Sulf-2, transcript levels of TNF-α­–induced chemokines CCL5, CX3CL1, CXCL11, CXCL9, and CXCL10 and adhesion molecules ICAM1, VCAM1,and PDPN decreased while levels of TNFAIP3 and TNFRSF11B were increasedmore than levels induced by TNF-α­ alone.

Reference

Siegel R, Singh A, Panipinto P, et al. Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of

synovial fibroblasts. Cell Mol Immunol. Published online September 7, 2022. doi:10.1038/s41423-022-00913-x