Researchers at Hospital for Special Surgery have identified a potential new target for drugs to treat patients with rheumatoid arthritis (RA), a protein known as IRHOM2. The finding could provide an effective and potentially less toxic alternative therapy to tumor necrosis factor-alpha blockers (TNF-blockers), the mainstay of treatment for rheumatoid arthritis, and could help patients who do not respond to this treatment. Efforts to develop drugs that hone in on this new target are underway.
"This study is an elegant example of the capacity of basic science cell biologists to work with translational rheumatologists to address a clinically relevant question at a basic level," said Jane Salmon, M.D., Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at Hospital for Special Surgery (HSS) in New York City, and an author of the study. "We have identified a clinically relevant target that can be applied to patients in the near term." The study will appear online, ahead of print, on January 25, in the Journal of Clinical Investigation and in the February 2013 print issue.
Rheumatoid arthritis, an autoimmune disease, is triggered, in large part, by TNF-alpha, a small signaling protein usually involved in launching protective systemic inflammatory responses. With excessive TNF production, however, immune cells can become activated inappropriately and cause tissue inflammation. This produces a number of diseases, including RA. While TNF-blockers help many RA patients, these treatments are very expensive, and some patients do not respond. For this reason, researchers have been searching for alternative targets in patients with inflammatory diseases against which drugs can be directed.
"TNF can be thought of as a balloon tethered to the surface of cells. To work, it must be cut loose by signaling scissors called TACE (TNF-alpha converting enzyme)," said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS. While blocking TACE could be another way to treat rheumatoid arthritis, researchers know this strategy would likely have side effects since patients lacking TACE are prone to skin infections and intestinal lesions.
Earlier this year, HSS investigators demonstrated that the TACE scissors are regulated by molecules called IRHOM1 and IRHOM2, which are thought to wrap around TACE and help it mature into functional scissors. They also demonstrated that mice that are genetically engineered to lack IRHOM2 lack functional TACE on the surface of their immune cells and don't release TNF. Surprisingly, these mice are healthy, and do not develop skin or intestinal defects.
In the current study, HSS researchers set out to investigate why this paradox exists. After examining tissues of IRHOM2-deficient mice, they found that IRHOM2 regulates TACE on immune cells, whereas IRHOM1 is responsible for helping TACE mature elsewhere in the body, such as in brain, heart, kidney, liver, lung and spleen cells. "IRHOM2 appears to have a more restrictive and exclusive function in immune cells," said Dr. Blobel.