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Caught red-handed. Antibodies to GPI accumulate in the joints of the mouse on the left. The mouse on the right received different antibodies.

Tracking a New Suspect in Arthritis

The crime is rheumatoid arthritis, the suspect a common enzyme called GPI. The latest break in the case is a pair of new studies showing that GPI has the means and opportunity to attack joints. The finding may offer a new way of understanding and treating arthritis.

Rheumatoid arthritis--in which the body's own defenses damage the joints--afflicts more than 2 million people in the United States alone. Until 1996, the best way to study the disease was to use arthritic mice that make extra antibodies against collagen, a major component of joint cartilage. Then, researchers engineered mice with antibodies to GPI (for glucose-6-phosphate isomerase), an enzyme that helps release energy from sugar. The engineered mice also have arthritis, raising the possibility that the disease is caused by an attack not on collagen but on the more widespread GPI.

Now, two teams of researchers report further links between GPI and cartilage in the April issue of Nature Immunology. A team led by Paul Allen, of Washington University School of Medicine in St. Louis, used positron emission tomography (PET) to follow the fate of radioactively labeled GPI antibodies. Minutes after the researchers injected the antibodies into normal mice, the paw joints started to glow. This rapid accumulation of antibodies matches the course of the disease in humans, where pain usually starts in the hands or feet.

Another team, led by Christophe Benoist at Harvard Medical School in Boston, found that the GPI antibodies attracted a compound known as C3. It kicks off an inflammatory response that most tissues can quench with membrane-bound proteins called inactivators. But joint cartilage, which lacks inactivators, can't stop the inflammation, the team reports.

The findings are important because they show how antibodies to a widespread molecule can cause a localized disease, says Toshio Hirano, a molecular oncologist at the Osaka University Graduate School of Medicine in Japan. But the researchers haven't presented enough evidence to convict GPI or to get collagen off the hook, he says. The real culprit may be a combination of the two or another, still unidentified, molecule. In any event, the research will allow scientists to widen the dragnet for new explanations and drug targets.

Related sites
The basics of rheumatoid arthritis
Paul Allen's home page
Christophe Benoist's home page