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Rheumatoid arthritis research finds key protein that could be targeted in future treatment

Local researchers have identified a protein playing a critical role in the inflammation damage caused by rheumatoid arthritis.

Now they hope their discovery might help treatments of a condition that afflicts 1.5 million Americans.

The findings of the role of protein sulfatase-2 shed more light on the molecular processes that drive inflammation, according to a study at Washington State University’s College of Pharmacy and Pharmaceutical Sciences.

Published in the journal Cellular & Molecular Immunology, the research brings out new information about sulfatase-2, said senior author Salah Ahmed, a WSU pharmaceutical sciences professor in Spokane.

A different protein known as a factor in the disease’s inflammation, tumor necrosis factor-alpha – or TNF-alpha – is today often targeted by drugs. However, the researchers found that sulfatase-2 is somehow tied into TNF-alpha’s role in causing inflammation, which could mean alternative therapies aimed at sulfatase-2 instead.

“TNF-alpha is one of the main inflammatory proteins that drive rheumatoid arthritis and is targeted by many currently available therapies,” Ahmed said.

“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.”

Rheumatoid arthritis is a chronic condition in which the immune system attacks the body’s own joint tissues.

Although sulfatases such as sulfatase-2 have been extensively studied for their roles in different types of cancer, Ahmed said there hasn’t been extensive research on how they might link to autoimmune diseases such as rheumatoid arthritis, so the WSU research is new.

“Yes, the sulfatase-2 protein has been identified to play a role in cancer, but its role in autoimmune disease and in particular for rheumatoid arthritis is not well described or not known,” he said.

“What we found in this research is this protein called sulfatase-2 really helps TNF in causing inflammation. What we initially observed was that the expression level of this protein, or the amount of this sulfatase-2, was very high in the samples we got from arthritis patients whether it was tissues or serum samples … it was noticeably higher compared with a healthy population.”

He said researchers studied the patients’ individual cells and the cells’ behavior when activated in culture dishes.

“We removed this protein sulfatase-2, and what we found was these cells were responding less to TNF-induced inflammation, so TNF-alpha’s ability to cause inflammation was mildly reduced because the sulfatase-2 was not there. That made us believe that sulfatase-2 is playing some kind of role in TNF-alpha-induced inflammation.”

First author Ruby Siegel, a Ph.D. graduate in the WSU college, said the research team explored the idea surrounding the sulfatase-2 protein as applied to 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,” Siegel said in a news release.

“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.”

Ahmed said future drug treatments might somehow inhibit the function of sulfatase-2, then most likely, that would limit the inflammation caused by TNF-Alpha. But more study is needed.

“We have to see how it works in animal models of arthritis, if we remove the protein, to see if animals have less severe arthritis. Then, there is an opportunity to explore this for therapy purposes.”

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