Novel therapeutic target identified in fight against Rheumatoid Arthritis

September 16, 2003

A team of scientists, led by Toshihiro Nakajima at the St Marianna University School of Medicine in Japan, has identified an exciting therapeutic target that may lead to the development of new treatments for Rheumatoid Arthritis (RA).

As published in the latest edition of Genes and Development, the scientists report the discovery of 'synoviolin', an enzyme that is found in abnormally high levels in diseased joints. High levels of synoviolin are found to cause an overgrowth of joint-destroying synovial cells, a key clinical feature of RA. By reducing levels of synoviolin, scientists hope to halt the proliferation of synovial cells and the devastating progression of RA.

RA is one of the most common joint diseases, affecting approximately 0.5-1.0% of the adult population worldwide. The progressive joint destruction, which mainly targets the small joints of the hands and feet, eventually results in severe movement disability. The clinical features of RA include chronic inflammation of the synovium, or lining of the joint, accompanied by the overgrowth of synovial cells, a condition known as synovial hyperplasia. This mass of synovial cells, or 'pannus', eventually invades and destroys the cartilage and bone within the joint. Clearly, understanding the factors that regulate synovial hyperplasia are key to designing new therapies to treat RA.

Dr Nakajima and colleagues set out to identify proteins found in synovial cells from rheumatoid joints, with the hope of discovering novel pathogenic factors involved in RA. Using an antibody screening approach, the scientists identified synoviolin as an enzyme that is upregulated in synovial tissues from RA patients. To elucidate the function of synoviolin, the team engineered mice that produced an excess of synoviolin. Significantly, these mice developed spontaneous arthritic joint disease, suggesting that too much synoviolin is indeed an important factor in the development of RA. They also generated mice with half the normal amount of synoviolin. When these mice were treated with a protocol that induces arthritis in normal mice, the 'low-synoviolin' mice were protected from the arthritis. This result firmly identified synoviolin as a key player in RA pathology.

The scientists went on uncover the cellular mechanism by which altered levels of synoviolin could influence joint pathology. By careful analysis of the engineered mice, they showed that synovial hyperplasia was prevented in the low-synoviolin mice because of increased synovial cell suicide or 'apoptosis'. Apoptosis is a vital protective mechanism against the overproduction of diseased or unwanted cells. On the other hand, synovial cell apoptosis was significantly impaired in mice overexpressing synoviolin, promoting synovial hypoplasia and ultimately, joint disease.

This research demonstrates the significance of synoviolin in regulating synovial hyperplasia and ultimately joint destruction in RA. It offers new insights into the etiology of RA and a novel target for innovative RA therapies. Future research will undoubtedly be focused on designing reagents to reduce the amount or inhibit the activity of synoviolin in diseased joints.
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Cold Spring Harbor Laboratory

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