UNC Researchers Reduce Arthritis Severity By Turning Off Molecular Switch

November 02, 1998

CHAPEL HILL, N.C. --In a scientific first, researchers at the University of North Carolina at Chapel Hill have reduced the severity of arthritis by turning off a molecular switch, a gene called NF-kappa B.

A report published Nov. 10 in the Proceedings of the National Academy of Sciences says the findings, based on experiments in laboratory rats, establish an important molecular mechanism in human rheumatoid arthritis. The findings demonstrate the feasibility of new ways to treat the disease, including gene therapy.

"These findings underscore NF-kappa B as a very attractive target for arthritis treatments, including a new generation of drugs targeted specifically to the molecule," says the team's leader, Dr. Sergei S. Makarov, research assistant professor of medicine at the UNC-CH School of Medicine and the Thurston Arthritis Research Center.

"In rheumatoid arthritis, the delicate synovial joint lining dramatically expands and transforms into an aggressive, tumor-like structure that invades and erodes the joint," Makarov says. "We started studying the role for NF-kappa B in arthritis because it controls the expression of numerous inflammatory genes, and we knew that it's activated within the arthritic synovium. Around that time, our collaborator, Dr. Al Baldwin, published his pioneer study demonstrating that activated NF-kappa B is needed to protect cancer cells in vitro from apoptosis, or programmed cell death."

From their subsequent in vitro studies, Makarov and his colleagues learned that similar mechanisms might operate in rheumatoid arthritis. "We found that inflammatory stimuli caused activation of NF-kappa B inside the cells from arthritic joints, rendering them resistant to apoptosis. It seemed that the more inflammation you had, the more protected those cells were against apoptosis," he says.

"We then predicted that if you block NF-kappa B in the arthritic joint, inflammation would go down, the cells would no longer be protected against apoptosis and they would be highly sensitive to cell death. That prediction actually occurred."

Researchers tested several strategies to inhibit NF-kappa B in animal arthritis. In one approach, they constructed a harmless artificial virus for delivering the gene of super-repressor I-kappa B. When injected into the arthritic rat joint, the virus infected the synovial cells, causing them to produce super-repressor I-kappa B and inactivate NF-kappa B, Makarov says.

"Using this approach, we effectively blocked NF kappa B and got a dramatic increase in apoptosis of inflamed synovial tissue," he says. "It appears that by targeting NF-kappa B in the joint, we benefit by blocking inflammation and accelerating apoptosis in the synovium. That's the way to make this tissue shrink."

The study also yielded an unexpected result. Researchers found that blocking NF-kappa B activation in one joint drastically inhibited the disease not only in treated joints, but also in the opposite, untreated joints. Although the mechanisms for this effect remain unclear, the researchers say it indicates systemic therapeutic effects of local treatment.

Makarov points out that human rheumatoid arthritis is a disease of multiple joints, seldom limited to a single type of joint or to one side of the body. He says the new findings suggest that successful systemic treatment may be possible by gene therapy limited to the most severely involved joints.

The study was a collaboration between UNC-CH and the Glaxo-Wellcome Research Institute. Alexei Miagkov, the first author on the paper, is a graduate student in Makarov's lab. Other UNC-CH collaborators include Dmitry V. Kovalenko, also a graduate student from Makarov's lab, and Dr. Albert S. Baldwin, associate professor of biology and associate director of basic research at the university's Lineberger Comprehensive Cancer Center. The team from Glaxo-Wellcome includes Chadwick Brown and Drs. John Didsbury, John Cogswell and Stephen Stimpson.
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Note to media: Dr. Sergei S. Makaraov will be available for interviews until Friday, Nov. 6, and after Friday, Nov. 13. He can be reached at 919-966-9565. From Nov. 8-12, he can be reached in San Diego, Calif., at the American College of Rheumatology meeting, at (619) 525-5635. His email address is smak@med.unc.edu.

The author of this release, Leslie H. Lang, can be reached at (919) 843-9687. Lang's email address is leslie_lang@med.unc.edu.
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University of North Carolina Health Care

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