Researchers from Cardiff University have uncovered a molecular pathway that plays a pivotal role in the onset of arthritis. Their research, published this week in Arthritis Research & Therapy, could aid in the discovery of novel targets for arthritis drugs.
The researchers found that inhibiting the enzyme PKR could prevent two processes central to the onset of arthritis: the production and activation of enzymes that break down connective tissue; and the release from cartilage of one of its principal constituents, proteoglycan.
They said: "Collectively these results support our hypothesis that PKR is implicated in the cartilage degradation that occurs in arthritic disease."
Despite the differences between osteoarthritis and rheumatoid arthritis, it is likely that similar molecular pathways can cause the degradation of cartilage in both diseases. Cartilage degradation results from an imbalance of enzymes that break down connective tissue and their inhibitors. In particular, activity levels of the enzymes MMP-2 and MMP-9 are frequently increased in the cartilage of people suffering from osteoarthritis.
The research team, led by Dr Sophie Gilbert, cultured cartilage cells in vitro. They then stimulated the cells with two molecules, TNF-a and C2-ceramide. The molecules simulated arthritic processes, increasing the release of proteoglycan and the production and activation of MMPs.
The researchers then repeated the experiment, but inhibited PKR at the same time. This time they found that there was no increase in the activation of MMP-2 or MMP–9 and that the release of proteoglycan was significantly reduced.
Their results imply that PKR is involved in the molecular pathways, stimulated by TNF-a and C2-ceramide, that are implicated in the progression of arthritis, since the simulation of arthritis was prevented by inhibiting PKR.
Arthritis is a common problem worldwide. Both osteoarthritis and rheumatoid arthritis cause joint pain and stiffness, which can result in severe pain and disability. Osteoarthritis is the most common form of the disease, affecting more than 2 million Britons and 20 million Americans.
As yet there is no cure for arthritis, and no effective treatments to repair damaged cartilage. The researchers hope that, through understanding more about the molecular pathway in which PKR is involved, they will be able to discover new drug targets for the treatment of arthritis.
This release is based on the following article:
Does protein kinase R mediate TNF-a- and ceramide-induced increases in expression and activation of matrix metalloproteinases in articular cartilage by a novel mechanism?Sophie J Gilbert, Victor C Duance and Deborah J MasonArthritis Res Ther 2004, 6:R46-R55Published 12 November 2003
Upon publication this article will be available online at http://arthritis-research.com/content/6/1/R46, without barrier to access, as per Arthritis Research & Therapy's open access policy.
Arthritis Research & Therapy (http://www.arthritis-research.com) is published by BioMed Central (http://www.biomedcentral.com), an independent online publishing house committed to providing immediate free access to the peer-reviewed biological and medical research. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science. In addition to open-access original research, BioMed Central also publishes reviews and other subscription-based content.
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