Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Unexpected new mechanism behind rheumatoid arthritis

08.02.2011
A team of researchers at the University of Gothenburg, Sweden, has identified an enzyme that protects against inflammation and joint destruction. 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.

The article has been published in the Journal of Clinical Investigation (JCI). 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.

Researchers previously believed that this fatty acid played an important role in activating the proteins and could contribute to the functioning of inflammatory cells. There are now medicines that include substances that suppress the activity of GGTase-I with the aim of stopping the CAAX proteins from working. These substances are already being clinically tested on cancer patients, and researchers have also wondered whether they could 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,” says PhD 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,” 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 many different cell functions.
For more information, please contact:
Professor Martin Bergö, Institute of Medicine, Sahlgrenska Academy, tel: +46 (0)31 342 7858, mobile: +46 (0)73 312 2224, e-mail: martin.bergo@wlab.gu.se
PhD student Omar Khan, Institute of Medicine, Sahlgrenska Academy, +46(0)31 342 4723, e-mail: omar.khan@wlab.gu.se

Docent/consultant Maria Bokarewa, Institute of Medicine, Sahlgrenska Academy, tel: +46 (0)31 342 4021, mobile: +46 (0)70 651 3292, e-mail: maria.bokarewa@rheuma.gu.se

Bibliographic data
Journal: Journal of Clinical Investigation (JCI).
Title of article: Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Authors: Omar M. Khan, Mohamed X. Ibrahim, Ing-Marie Jonsson, Christin Karlsson, Meng Liu, Anna-Karin M. Sjogren, Mikael Brisslert, Sofia Andersson, Claes Ohlsson, Lillemor Mattsson Hultén, Maria Bokarewa and Martin O. Bergo

Helena Aaberg | idw
Further information:
http://www.gu.se
http://www.sahlgrenska.gu.se/digitalAssets/1327/1327114_khan_et_al_jci43758.pdf

Further reports about: CAAX GGTase-I Medicine Rac1 fatty acid inflammatory cells proteins rheumatoid arthritis

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>