Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have made an important discovery about the cause of joint damage in rheumatoid arthritis (RA), one of the most common and debilitating joint diseases. They have identified a new target for therapeutic development to slow or prevent joint damage, perhaps without the side effects of many current arthritis medications.

RA, a disease that affects an estimated 2.1 million Americans, is thought to occur when the body’s normally protective immune system mistakenly attacks the thin membrane that lines the joint. In healthy joints, that membrane, called the synovium, secretes a fluid that nourishes and lubricates the joint. “It is essential for joint function,” says David M. Lee, M.D., of Brigham and Women’s Hospital in Boston and lead author of the new study published in the journal Science. In RA, however, white blood cells of the immune system infiltrate the synovium. “We think these cells drive inflammation in the joint,” he says. “But at the same time, the synovium shows a number of other abnormal features. It overgrows and starts attaching to the bone and cartilage.” Unchecked, the synovial tissue can erode the cartilage and bone, leading to joint damage and malformation.

While inflammation has been blamed for this destructive process, Dr. Lee and his colleagues found another factor they suspect plays a crucial role: an adhesion molecule on cells of the synovium called cadherin-11. Adhesion molecules allow individual cells to stick together to form tissues, explains study author Michael B. Brenner, M.D., also of Brigham and Women’s. At normal levels, cadherin-11 enables the cells (synoviocytes) to adhere together to form the lining layer of the synovium. But when overgrowth of the synovium occurs, cadherin plays a key role in the destructive behavior of the synovium; namely, eroding the cartilage, which causes permanent destruction to the joint.

To confirm their suspicions, the researchers turned to mice that develop a disease model similar to human RA. When the mice were genetically altered so that their cells didn’t produce cadherin-11, the mice failed to develop arthritis or developed only very mild disease, the researchers found. Next, the researchers gave an agent that blocks cadherin-11 to RA-prone mice without the genetic alteration. Those mice, too, failed to develop the disease or developed only a mild case and – importantly – did not develop cartilage destruction. That destruction was aborted because by blocking the cadherin, the overactive synovium was not able to attach to and erode the cartilage.

“Whether we used a knockout mouse that lacked cadherin-11 or used a therapeutic to block it, a lack of cadherin-11 stopped the process,” says Dr. Brenner. Now that they’ve shown blocking cadherin-11 helps arthritis in mice, the next step will be to determine whether an agent to block an excess of the molecule has the same beneficial effect in people with RA.

If human studies confirm their findings, agents to block the adhesion molecule may one day present a new and perhaps safer way to treat RA. Most current medications for the disease work by suppressing or modifying the aberrant immune response. But in doing so, they can affect normal immunity and leave people open to infections. “Using agents that block cadherin-11 may be a safer way to treat, because it is targeted specifically to the joints and will not affect the immune system,” says Dr. Lee. Such agents may also be used in conjunction with other arthritis medications because they work in different ways.

Additional support for this research was provided by the Cogan Family Foundation, the Arthritis Foundation, the Riva Foundation and the Abbot Scholar Award in Rheumatology Research.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

###

Lee DM, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 2007; 315:1006-1010.