| Departments — Benchmarks | Winter 2007 |
Line of Attack  “For me a picture must be an amiable thing, joyous and pretty—yes, pretty! There are enough troublesome things in life,” the French impressionist Pierre-Auguste Renoir wrote, barely hinting at his own misfortune. Renoir struggled for decades with one of the most debilitating and disfiguring of diseases, rheumatoid arthritis. The disorder, which struck when he was 50, would slowly erode the cartilage and bone of his hands, shoulder, and feet and lay waste to other parts of his body. The great master had only his art—and the occasional visit to a spa—to see him through. A century later, there are various treatments for rheumatoid arthritis, but they do not always alleviate patients’ suffering. Most quell the immune system’s attack on the tissue lining the joints, a defining event in the disease. Yet this attack is but one aspect of a complex, often variable disease. In a surprising new twist, it now appears that, once attacked, the joint lining, or synovium, may not only ramp up inflammation in the joint but also begin to erode the cartilage. David Lee, an HMS assistant professor of medicine at Brigham and Women’s Hospital, and Michael Brenner, Theodore Bevier Bayles Professor of Medicine at the Brigham, have identified a protein that coordinates the synovium’s destructive activities. Their findings, published in the February 16 issue of Science, could usher in new treatments for the joint-wasting disease. A Joint Endeavor Several years ago Lee, Brenner, and colleagues identified a protein in the synovium, a delicate but dense wisp of cells, that makes the cells of the tissue stick together and form a compact, tightly organized structure. The discovery spurred Lee to explore the role of that protein, cadherin-11, in living animals, by comparing cadherin-11–knockout mice with wild types. In contrast to the wild-type synovium, with its neat rows of cells, that of the knockouts appeared sparse and desultory, confirming cadherin’s role in shaping the synovial tissue. When Lee and colleagues tried inducing rheumatoid arthritis in the cadherin-11–deprived mice, the animals barely showed signs of disease. Not only did they suffer less cartilage loss, but their levels of inflammation were about half those found in similarly treated wild-type animals. Lee and colleagues also tried blocking cadherin-11 in the wild types before inducing the disease. The mice resisted disease, much like the knockouts. These findings hold obvious implications for treating humans and point to the possibility that the principle underlying their approach—that tissues, once attacked by the immune system, may actually stoke inflammation—could have broader applicability. Casting Call Rheumatoid arthritis is thought to begin when the immune system attacks the synovium, though it is still not clear what causes this attack. Once inflamed, the synovium balloons, forming a thick, shroudlike structure, or pannus, that begins to chew its way along the cartilage-covered bone, initiating the destructive, bone-wasting phase of the disease. Brenner was intrigued by the synovium, especially as little is known about its structure, and decided to investigate further its role in the disease. The veil-like tissue is loaded with cells that respond quickly to infection. Brenner also was interested in the cadherins, cell-adhesion molecules that bind to one another instead of to different kinds of proteins. He found that cadherin-11 worked in the synovium and was responsible for prompting its cells to stick to one another and to line up in neat rows. The findings showed that the protein helped to organize the normal synovium and played a critical role in the formation of the pannus, not just its bloating—it was skimpier in the knockouts—but also its subsequent crawl along the bones: When cultured, the cells of the pannus migrated less than those of wild-type mice. Lee and Brenner believe that cadherin-11, in addition to allowing the cells of the synovium to bind to one another, directs the cells to migrate across and, eventually, to invade and destroy the cartilage. Its ability to instigate both inflammation and cartilage damage makes cadherin-11 an appealing drug target, either alone or with existing therapies. The new study could raise the profile of the cadherins, which have been, according to Brenner, “low-liers” in the medical world. “Can we take what we have learned about cadherin-11’s role in rheumatoid arthritis and think about other autoimmune and inflammatory diseases?” he asks. “The liver, the kidney, the heart, brain, and skin—to what degree do those tissues and the cell types in those tissues, and the cadherins on the cell types, influence the way those tissues respond to inflammation? Is this a model for looking at disease in other contexts?” Misia Landau is a senior science writer for Focus. Photo: © istockphoto.com/anne de Haas |
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