Researchers pinpoint enzyme involved in arthritis onset

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 molecule 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-alpha 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-alpha 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 mediated by PKR, 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-alpha 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 Mason
Arthritis Res Ther 2004, 6:R46-R55
Published 12 November 2003