Key Protein That Drives Rheumatoid Arthritis Damage

Rheumatoid arthritis is a chronic disease in which the immune system attacks the body’s own joint tissues, rheumatoid arthritis affects an estimated 1.5 million Americans.

A new discovery 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.

“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,” said senior author Salah-Uddin Ahmed. “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.”

“In rheumatoid arthritis, these normally quiescent cells get activated by TNF-alpha and other inflammatory molecules, and they take on this aggressive character,” said first author Ruby J. Siegel, a PhD graduate. “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.”

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-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.

“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.” Ahmed said.

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.


Ruby J. Siegel, Anil K. Singh, Paul M. Panipinto, Farheen S. Shaikh, Judy Vinh, Sang U. Han, H. Mark Kenney, Edward M. Schwarz, Cynthia S. Crowson, Sadik A. Khuder, Basil S. Khuder, David A. Fox, Salahuddin Ahmed. Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts. Cellular & Molecular Immunology, 2022; DOI: 10.1038/s41423-022-00913-x

Washington State University. “Key protein that drives rheumatoid arthritis damage.” ScienceDaily. ScienceDaily, 8 September 2022. <>.

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