Researchers say they have identified a protein known as sulfatase-2 that plays a critical role in the damage caused by rheumatoid arthritis, a chronic disease in which the immune system attacks the body’s own joint tissues. Rheumatoid arthritis affects an estimated 1.5 million Americans.

The team’s discovery “Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts”, published in Cellular and Molecular Immunology, sheds new light on the molecular processes that drive inflammation seen in rheumatoid arthritis. It could also someday lead to improved treatment of the disease, which currently has no cure.

“Extracellular sulfatase-2 (Sulf-2) influences receptor–ligand binding and subsequent signaling by chemokines and growth factors, yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis (RA),” wrote the investigators.

“In the present study, we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts (RASFs). Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice. RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated ~2500 genes compared to scrambled siRNA.

“This study identified a novel role of Sulf-2 in TNF-α signaling and the activation of RA synoviocytes, providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.”

One of the main inflammatory proteins

“Tumor necrosis factor-α—or TNF-α for short—is one of the main inflammatory proteins that drive rheumatoid arthritis and is targeted by many currently available therapies,” said senior author Salah-Uddin Ahmed, PhD, a professor in Washington State University’s (WSU) College of Pharmacy and Pharmaceutical Sciences. “However, over time patients can develop a resistance to these drugs, meaning they no longer work for them. That is why we were looking for previously undiscovered drug targets in TNF-α signaling, so basically proteins that it interacts with that may play a role.”

Though sulfatases such as sulfatase-2 have been extensively studied for their roles in different types of cancer, Ahmed said no one had looked at how they might be involved in inflammatory or autoimmune diseases such as rheumatoid arthritis.

The research team first explored this idea using cells called synovial fibroblasts, which line the joints and keep them lubricated to ensure fluid movement.

“In rheumatoid arthritis, these normally quiescent cells get activated by TNF-α and other inflammatory molecules, and they take on this aggressive character,” said first author Ruby J. Siegel, PhD, a postdoc in the WSU College of Pharmacy and Pharmaceutical Sciences. “They are not dying when they should, and they proliferate in a way that is almost tumor-like, forming this massive synovial tissue that should not be anywhere near that size and at the same time activating proteins that destroy cartilage and bone.”

Same inflammatory response not seen

Using the joint-lining cells of rheumatoid arthritis patients, they removed sulfatase-2 from one group of cells before stimulating all cells with the inflammatory TNF-α. What they found was that cells lacking sulfatase-2 did not show the same exaggerated inflammatory response to TNF-α as cells that were left intact.

“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,” Ahmed said. “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.”

Resulting from a series of experiments spanning four years, the researchers’ findings open the door to future animal studies to test the effectiveness of inhibiting sulfatase-2 to ease rheumatoid arthritis symptoms.

This could someday lead to the development of new combination therapies that along with other inflammatory proteins would also target sulfatase-2 to prevent bone loss, cartilage damage, and deformed joints. Such therapies could help address the shortcomings of currently available rheumatoid arthritis drugs, many of which come with significant side effects.


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