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Unexpected new mechanism behind rheumatoid arthritis
Date:2/7/2011

Tase-I in macrophages (a common type of inflammatory cell) led to the mice developing chronic inflammation with cartilage and bone erosion in the joints, very similar to rheumatoid arthritis in humans.

"We had to reassess the role that GGTase-I plays in the function of CAAX proteins, and found that one group of CAAX proteins could not only function quite normally in macrophages that didn't have any GGTase-I, but even increased in number and activity. This led to hyper-activation of the macrophages, which produced large quantities of inflammatory substances and, in turn, led to arthritis in the mice."

GGTase-I acts on over 50 different CAAX proteins. The study shows that just one of these proteins RAC1 appears to be behind the disorder. This means that one function of GGTase-I is to suppress the activity of RAC1 and protect mice from developing arthritis. The results suggest that medicines that inhibit GGTase-I might actually induce arthritis instead of providing a cure. This will be important information for the ongoing clinical trials with GGTase-I inhibitors in cancer patients.

"The study has also resulted in an effective and simple genetic mouse model for arthritis that can be used to study the effect of new medicines and identify the mechanisms involved in the development of the disorder," says Khan. "The next step is to try to decide whether and how GGTase-I and RAC1 are implicated in arthritis in humans."

CAAX PROTEINS

CAAX proteins are a collection of proteins in the cells that have the amino acid sequence C-A-A-X at one end. This sequence is a signal for the protein to attract a number of enzymes, including GGTase-I, which switches on a cholesterol-like fatty acid on the CAAX proteins. This enables the protein to bind to membranes in the cells, for example the inside of the membrane that surrounds the cell. CAAX proteins include RAS (a well-known cancer protein) and the RAC and RHO proteins, which are important for
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Contact: Omar Khan
omar.khan@wlab.gu.se
46-031-342-4723
University of Gothenburg
Source:Eurekalert

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