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Crippling a single protein combats arthritis

March 30, 2005 By Helen Pearson This article courtesy of Nature News.

Drugs that target a cartilage enzyme could treat joint decay.

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Knocking out a single gene in mice brings arthritis to a grinding halt, scientists have found. The discovery may herald treatments for people who suffer from the crippling disease.

Osteoarthritis occurs when the cushioning cartilage around joints gradually breaks down, triggering pain, stiffness or other symptoms. It affects more than half of people aged over 65. There are no drugs to halt the disease's onslaught, leaving patients dependent on painkillers or joint replacements.

Two studies published in Nature this week could change this bleak scenario1,2. The researchers investigated a family of enzymes, called aggrecanases, that are thought to contribute to osteoarthritis by chewing up a vital component of cartilage that makes it tough and elastic.

It almost seems like a dream target for a drug company.
Christopher Evans
Orthopaedic specialist, Brigham and Women's Hospital in Boston
The teams showed that mice genetically engineered to lack a working form of one such enzyme, ADAMTS5, seem impervious to arthritis. The groups were led by Amanda Fosang at the University of Melbourne, Australia, and Elisabeth Morris at Wyeth Research in Cambridge, Massachusetts.

Pinning a target

It's the first time that researchers have managed to pinpoint one specific protein that drives the joints' decay. "Various enzymes come and go and all turn out to be dead ends," says orthopaedic specialist Christopher Evans of Brigham and Women's Hospital in Boston. "But now we might be on to something."

The discovery could lead to drugs that prevent cartilage from crumbling. Scientists at Wyeth are already searching for small molecules that can do this by interfering with the ADAMTS5 enzyme. "We're working hard on that," Morris says.

The researchers are particularly hopeful because the mice lacking the working enzyme showed no signs of problems elsewhere in their bodies. This suggests that drugs that inhibit the protein would have few of the side-effects that doom many prototype therapies. "It almost seems like a dream target for a drug company," Evans says.

Although blocking this one protein appears to prevent cartilage destruction, researchers think there may still be several others that are important in triggering osteoarthritis. The disease is accelerated by age, joint injuries and being overweight.

Morris's team mimicked osteoarthritis in mice by injuring their joints, but Fosang's team simulated arthritis by provoking inflammation. The latter is a condition more akin to rheumatoid arthritis, in which the immune system attacks joint tissues, but wiping out ADAMTS5 still prevented cartilage decay.

This suggests that drugs that block this enzyme might benefit rheumatoid arthritis patients. In such a case, however, they would probably have to be administered with other drugs that stop the inflammation driving the disease, Evans says.

References

  1. Glasson S. S., et al. Nature, 433. 644 - 648 (2005).
  2. Stanton H., et al. Nature, 433. 648 - 652 (2005).

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