Study Links Sulfatase to Rheumatoid Arthritis

Researchers at Washington State University (WSU) have identified a protein 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. The findings may lead to improved treatment of the disease, which currently has no cure and affects an estimated 1.5 million Americans.

The discovery was the result of research looking at the molecular processes that drive inflammation seen in rheumatoid arthritis. “Tumor necrosis factor-alpha—or TNF-alpha for short—is one of the main inflammatory proteins that drive rheumatoid arthritis and is targeted by many currently available therapies,” says senior author Salah-Uddin Ahmed, a professor in WSU’s  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-alpha signaling, so basically proteins that it interacts with that may play a role.”

The study—published recently in the journal Cellular & Molecular Immunology—zeroed in on sulfatase-2 after a number of experiments spanning four years. Though sulfatases 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 potential 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-alpha and other inflammatory molecules, and they take on this aggressive character,” says Ruby J. Siegel, a PhD graduate 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.”

To test their theory, the team removed sulfatase-2 from one group of joint-lining cells taken from rheumatoid arthritis patients, before stimulating all cells with the inflammatory TNF-alpha. What they found was that cells lacking sulfatase-2 did not show the same exaggerated inflammatory response to TNF-alpha 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-alpha relies on sulfatase-2 to drive inflammation, because as soon as we removed sulfatase-2 the inflammatory effects of TNF-alpha were markedly reduced.”

The findings open the door to future animal studies to test the effectiveness of inhibiting sulfatase-2 to ease rheumatoid arthritis symptoms. This line of research could eventually lead to the development of new combination therapies that would target sulfatase-2 along with other inflammatory proteins 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. “These drugs shut off TNF-alpha in your whole body, but it does have important immune functions,” Siegel said, adding that patients who take these types of drugs are more susceptible to infection and have an increased risk of developing cancer with long-term use. TNF-alpha inhibitors are not effective in all people and are not recommended for patients with certain other health conditions.