WEDNESDAY, March 28, 2007 (HealthDay News) -- In the quest for the causes of and potential treatments for rheumatoid arthritis, Japanese researchers have identified a protein that could be a target for future therapy.
Rheumatoid arthritis (RA) is a chronic and disabling autoimmune disease that first attacks the fluid that surrounds the joints, causing it to thicken and grow abnormally, damaging the joints and surrounding cartilage rather than protecting them. More than 2 million Americans suffer from the illness, according to the Arthritis Foundation.
By identifying a protein that appears to be one of the culprits in the unhealthy buildup of this fluid, which is called synovial fluid, Dr. Yasushi Miura and his colleagues at Kobe University School of Medicine hope that a new, targeted medication can be developed to treat the disease.
"The protein Decoy receptor 3 (DcR3) is one of the pathological factors of RA and can be a new therapeutic target for treatment," said Miura, an associate professor in the division of orthopedic sciences at the medical school.
His findings are published in the April issue of Arthritis & Rheumatism, the journal of the American College of Rheumatology.
DcR3 is a member of the large tumor necrosis factor receptor (TNFR) "super family," which has been identified in the last decade as important in the regulation of cell growth and cell death, fundamental processes in biology, said Dr. Robert Hoffman, director of the division of rheumatology and immunology at the University of Miami Miller School of Medicine in Florida.
"We have known of the importance of cell growth and cell death in studying cancer but more recently have found that it is also important in autoimmune diseases like RA and lupus," he said.
It was the similarity between the growth of malignant tumors and the abnormal growth of synovial tissue, called hyperplasia, that sparked Miura's research into DcR3 and rheumatoid arthritis. DcR3 is known to be produced in tumor cells, including lung and colon cancers.
What Miura and his colleagues found was that DcR3 works with another member of the TNFR family to slow the normal cell death of synovial fluid cells, resulting in the hyperplasia that causes some of the inflammation characteristic of rheumatoid arthritis.
Hoffman said: "This is a novel application of the connection between this specific member of the TNFR super family and RA, and studies like this are how we advance science. But it is currently a giant leap to suggest that this could be a therapy for RA."
For their study, Miura and his colleagues isolated and cultured cells from synovial fluid from19 patients with rheumatoid arthritis, obtained during total knee replacement surgery. For comparison, they also extracted synovial fluid cells in the same manner from 14 patients with osteoarthritis.
The researchers then exposed the synovial fluid cells to another TNFR protein called Fas, which induces cell death, called apoptosis. Finally, the cells were incubated with a pro-inflammatory member of the TNFR family, called TNFa. The TNFR family includes proteins that both induce and retard cell death, Miura explained.
While DcR3 was present in the same amounts in the synovial fluid cells of both the rheumatoid arthritis and osteoarthritis patients, when the TNFa was introduced, DcR3 production increased in the cells of the RA patients, slowing down the Fas-induced cell death. The rate of cell death did not change in the fluid of the osteoarthritis patients, perhaps, Miura suggested, because the TNFa levels were higher in the fluid of RA patients to begin with.
Miura said the results show that DcR3 acts in conjunction with TNFa to suppress the cell death necessary to keep synovial fluid healthy, and research aimed at reducing the amount of DcR3 in the synovial fluid in rheumatoid arthritis patients could be productive.
Dr. Stephen Lindsey, head of rheumatology at the Ochsner Clinic Foundation in Baton Rouge, La., said, "We are always looking for better and more specific targets to control immune response, and this study is very intriguing."
Lindsey said there are drugs available that inhibit those proteins that suppress cell death, but because they are "global," rather than targeted to particular proteins, there are many side effects, including infection.
The Arthritis Foundation offers more information on rheumatoid arthritis.
SOURCES: Yasushi Miura, M.D., Ph.D., Kobe University School of Medicine, Kobe, Japan; Stephen Lindsey, M.D., head of rheumatology, Ochsner Clinic Foundation, Baton Rouge, La.; Robert Hoffman, M.D., professor of medicine, microbiology and immunology, director of the division of rheumatology and immunology, University of Miami Miller School of Medicine, Florida; April 2007, Arthritis & Rheumatism
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