Understanding rheumatoid arthritis
Scientists at the University of Gothenburg in Sweden have taken a step closer to understanding rheumatoid arthritis after discovering a new mechanism behind the disease. Rheumatoid arthritis is a chronic, systemic inflammatory disorder that afflicts about 1% of the world's population, but whose cause remains a mystery. The study, funded in part by the EU through a EUR 1.6 million European Research Council (ERC) Starting Investigator Grant, is published in the Journal of Clinical Investigation. Researchers in Sweden have identified an enzyme that protects against inflammation and joint destruction. They made the discovery by blocking production of the enzyme GGTase-I in transgenic mice. They believe that this unexpected result could lead to the identification of new mechanisms that control the development of inflammatory disorders, as well as new therapies. 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. Until now, researchers thought that this enzyme played an important role in activating the proteins and could contribute to the functioning of inflammatory cells. Indeed, there are already medicines on the market that include substances that suppress the activity of GGTase-I with the aim of inhibiting the function of CAAX proteins. These substances are being clinically tested on cancer patients and researchers had begun to wonder whether they could also be used to alleviate inflammatory disorders such as rheumatoid arthritis. However, treatment with substances that inhibit GGTase-I has often been non-specific, making it difficult for researchers to assess the real potential of GGTase-I as a drug target. 'We therefore developed genetic strategies in transgenic mice to switch off the gene that codes for GGTase-I,' explained Omar Khan who led the study with Professor Martin Bergö and consultant Maria Bokarewa from the university's 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,' he said. However, the results from this experiment 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. Hence, as Mr Khan commented: '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.' According to him, 'This led to hyper-activation of the macrophages, which produced large quantities of inflammatory substances and, in turn, led to arthritis in the mice.' Dr Khan added that 'GGTase-I acts on over 50 different CAAX proteins' and this study showed 'that just one of these proteins - RAC1 - appears to be behind the disorder'. He said, 'This means that one function of GGTase-I is to suppress the activity of RAC1 and protect mice from developing arthritis.' Therefore, 'the results suggest that medicines that inhibit GGTase-I might actually induce arthritis instead of providing a cure,' he noted. 'This will be important information for the ongoing clinical trials with GGTase-I inhibitors in cancer patients.' The researcher pointed out that the study had 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'. Mr Khan therefore concluded that 'the next step is to try to decide whether and how GGTase-I and RAC1 are implicated in arthritis in humans'.For more information, please visit: University of Gothenburg:http://www.gu.se/englishEuropean Research Council (ERC) Starting Investigator Grant:http://erc.europa.eu/index.cfm?fuseaction=page.display&topicID=65
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