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Spotlight on Research 2011
NIAMS Scientists Find Potential New Target for Rheumatoid Arthritis Treatment
A new study supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has identified a potential way to halt the cartilage destruction that occurs with rheumatoid arthritis (RA) without suppressing the immune system, as current therapies do. The work was published in the Proceedings of the National Academy of Sciences USA.
The technique involves blocking a molecule called cadherin-11 (cad-11) found on cells of the synovium, the membrane that lines the joint. In healthy joints, the membrane is thin and secretes lubricating substances. But in people with RA, the synovium becomes inflamed and enlarged, and begins to destroy the cartilage.
Traditionally, treatment has involved suppressing the immune system, which, for many people, eases pain and inflammation and slows or stops cartilage damage. But, current therapies donít work for everyone, and suppressing the immune system leaves patients open to the risk of infection and increases the possibility of certain cancers. These risks prompted researchers led by NIAMS-supported investigator Michael Brenner, M.D., to look for a targeted, localized treatment aimed at protecting joint tissue directly.
Earlier research by the group suggested cad-11 was a potential target. The scientists discovered that cad-11expression on cells of the synovium, called synovial fibroblasts, makes those cells more degradative and invasive. Cad-11, they found, also causes the cells to produce more matrix metalloproteinases (MMP), enzymes that degrade cartilage. Thus, they believed that if cad-11 were removed or blocked, there might be less damage to the cartilage.
To test their theory, the scientists turned to a mouse model of RA. First, they took advantage of mice engineered to lack the gene that encodes cad-11. When inflammatory arthritis was induced, these mice did not show the cartilage damage that occurred in mice with the gene. Further, they administered an antibody that blocks cad-11 in a therapeutic trial in mice and found that the inflammatory process was reduced, as shown by reduced swelling in the joint, says Dr. Brenner, Theodore Bayles Professor of Medicine at Harvard Medical School and Chief of the Division of Rheumatology, Immunology, and Allergy at Brigham and Womenís Hospital.
While research so far has been confined to animals, Dr. Brenner hopes that the findings will translate to people with RA. Already, he says, an agent to block cad-11, that would likely be injected or infused, is in development. If clinical trials eventually prove such a therapy effective in people, it might be used in place of current therapies to reduce side effects, or in combination with other therapies to increase their effectiveness without increasing their risks.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. 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 the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.
Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, Leon L, Lee SY, Lee DM, Brenner MB. Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8402-7. Epub 2011 May 2. PMID: 21536877; PMCID: PMC3100978.