Discovery of Pivotal Pathway to Regulating Inflammatory Arthritis

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Discovery of Pivotal Pathway to Regulating Inflammatory Arthritis

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INFLAMMATORY ARTHRITIS

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Researchers have discovered that blocking an intracellular signaling

enzyme in a key pathway may lead to effective new treatments to fight

rheumatoid arthritis.

Newswise — 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 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 J. , Ph.D., of the University of

Massachusetts School of Medicine, and 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 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.