An enzyme that protects against inflammation and joint destruction has been identified by a team of researchers at the University of Gotenburg, Sweden.
Made when the researchers blocked production of the enzyme GGTase-I in transgenic mice, this unexpected discovery could lead to the identification of new mechanisms that control the development of inflammatory disorders, as well as new medicines.
GGTase-I is found in all cells but is particularly important for the function of so-called CAAX proteins in inflammatory cells. GGTase-I attaches a cholesterol-like fatty acid on the CAAX proteins.
“We therefore developed genetic strategies in transgenic mice to switch off the gene that codes for GGTase-I,” said student Omar Khan who is heading up the study along with professor Martin Bergö and co-worker docent/consultant Maria Bokarewa from the Institute of Medicine.
“This allowed us to investigate whether a complete blockade of GGTase-I can inhibit the development of inflammatory disorders and whether there are any side-effects.”
However, the results were quite the opposite of what the researchers were expecting. Instead of inhibiting inflammation, the deficiency of GGTase-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,” said Khan.
The study has been published in the Journal of Clinical Investigation (JCI).