Researchers at the University of California, San Diego (UCSD) School of Medicine have discovered that blocking an intracellular signaling enzyme in a key pathway may lead to effective new treatments to fight rheumatoid arthritis. Their findings will be published in the March 20 issue of Proceedings of the National Academy of Science (PNAS.)

“This discovery is exciting because it could potentially lead to less expensive and, hopefully, safer drugs to treat rheumatoid arthritis,” said Gary S. Firestein, M.D., Professor of Medicine, Chief of the Division of Rheumatology, Allergy and Immunology, and Director of UCSD’s Clinical Investigation Institute.

Patients with rheumatoid arthritis are commonly treated with a class of drugs that treat symptoms by blocking the action of a protein called tumor necrosis factor (TNF). TNF is a component of the body’s immune system that triggers inflammation during normal immune responses. When overproduced, TNF can lead to excessive inflammation such as that experienced by patients with rheumatoid arthritis. However, such treatments can suppress normal immune responses, must be administered by injection rather than taken orally, and are very expensive.

For many years, researchers have explored developing better therapeutic targets by blocking the function of a family of enzymes called p38 MAP kinase, which regulate cytokines -  proetin secreted in response to stress that regulate inflammation -  in patients with arthritis.

“In the molecular machinery that controls the pathways ‘turned on’ by stress, p38 acts like a switch on a train track,” said Firestein. “Turning off the p38 switch blocks all responses -  good or bad -  moving along this pathway. Our group has found that one of the ‘switches’  -  or kinase regulators -  upstream can block abnormal inflammation that results in arthritis while permitting a normal response to infection.”

Tomoyuki Inoue, Ph.D., of UCSD’s Division of Rheumatology, Allergy and Immunology and first author of the study, found that blocking the kinase regulator called MKK3, could, in effect, prevent the innate immune responses in the joint and block production of the cytokines that cause rheumatoid arthritis.

The researchers first demonstrated this alternative approach to inhibiting p38 MAP kinase by targeting MKK3 in vitro. They then studied arthritis in mice lacking the MKK3 gene developed by fundamental biologists Roger J. David, Ph.D., of the University of Massachusetts School of Medicine, and Richard A. Flavell, Ph.D., Yale University School of Medicine. The genetically modified mice displayed dramatically lower levels of inflammation.

Their research demonstrated that the selective MKK3 deficiency suppressed inflammatory arthritis and cytokine production, while allowing host defense mechanisms to remain intact.

“These studies show that it is possible to determine the hierarchy and organization of signal transduction proteins so that targeted therapies can be developed for disease while leaving many normal cellular functions intact,” said Inoue. “They also show how basic and clinical researchers can work together to begin translating basic science discoveries into new treatments.”

Additional contributors include David L. Boyle, Ph.D., Maripat Coor and Deepa Hammaker, UCSD Division of Rheumatology, Allergy and Immunology. The research was funded by grants from the National Institutes of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.