New target to battle rheumatoid arthritis identified

Researchers have uncovered the mechanism by which a cell signalling pathway contributes to the development of rheumatoid arthritis (RA). The study led by researchers at Hospital for Special Surgery, also provides proof that drugs under development for diseases such as cancer could potentially be used to treat RA. Rheumatoid arthritis is a systemic inflammatory autoimmune disease that can be crippling and impacts over a million adults in the United States. "We uncovered a novel mechanism by which the Notch pathway could contribute to RA,” said Xiaoyu Hu, M.D., Ph.D., a research scientist at Hospital for Special Surgery in New York City and principal investigator of the study. Before this study was carried out, researchers knew that an intracellular molecular pathway called Notch is involved in diseases such as cancer. Last year, other scientists also conducted a genome wide association study to identify genes that were associated to the development of rheumatoid arthritis. They found that a certain mutation in a gene involved in the Notch pathway puts patients at risk for RA, but nobody knew just how it was involved. "We were intrigued. Nothing has been known about how the Notch pathway is important to RA," said Hu. Working with researchers at other institutions in the United States and abroad, HSS investigators started putting two and two together and noted that if Notch might be involved in a misfiring of the immune system that is a common observation in case of RA. After that, the researchers designed experiments to test whether the Notch pathway had an influence on macrophages, a type of white blood cell that is most commonly known for gobbling up pathogens but at the same time can also cause inflammation. Macrophages that go ‘awry’ possess widespread pro-inflammatory and destructive capabilities that can critically contribute to acute and chronic rheumatoid arthritis. "In the case of RA, inflammatory macrophages attack joints and they produce inflammatory mediators that basically sustain inflammation in joints," said Hu. In experiments, researchers found that knockout mice that lack the ‘Notch’ pathway in macrophages were unable to produce certain type of macrophages and displayed a lesser inflammatory phenotype. "Notch is essential for the development and function of a cell type called the inflammatory macrophages and if this pathway is missing in mice, then you don``t get good differentiation of the inflammatory macrophages," said Hu. In short, the ‘Notch’ pathway is essential for the differentiation and function of inflammatory macrophages and these macrophages are critical for human RA pathogenesis. In a series of test tube studies, the researchers flushed out the specifics of how Notch influences the molecular cascade leading to generation of inflammatory macrophage. In another experiment, the investigators used an inhibitor of the Notch pathway called ‘GSI-34’ that is under development and showed that this drug could constrain the function of macrophages. The researchers revealed that the study provides the first explanation of how Notch contributes to rheumatoid arthritis pathogenesis. For the first time, it also shows that the investigational Notch inhibitors under development for cancer and Alzheimer``s could potentially be used to treat RA. Several Notch inhibitors are under development by various companies and a few are presently in Phase III trials. "Before this study, the Notch pathway has been implicated mainly in cancer, but in this study we define how it is connected to RA," Hu added. The study is published online in advance of print in Nature Immunology.