Study leader, Xiaoyu Hu, M.D., Ph.D., a research scientist at Hospital for Special Surgery in New York City declared: "We uncovered a novel mechanism by which the Notch pathway could contribute to RA."
The team was aware of the fact that Notch, an intracellular molecular pathway plays a role in diseases like cancer before they embarked on their study due to the fact a study of another research team discovered in 2011 that a certain mutation in a gene involved in the Notch pathway places patients at risk for RA. However, the study was unable to reveal the mechanism.
Hu said: "We were intrigued. Nothing has been known about how the Notch pathway is important to RA." Hu started to collaborate with other U.S. scientists and scientists from abroad and they discovered that Notch could potentially be involved in a misfiring of the immune system, which is frequently observed in RA.
They developed methods to evaluate a potential impact of the Notch pathway on macrophages, i.e. white blood cells within tissues that ingest pathogens and can cause inflammation. Macrophages that have become abnormal possess attributes of being destructive and causing widespread inflammations, which can strongly contribute to acute and chronic rheumatoid arthritis. Dr. Hu explains: "In the case of RA, inflammatory macrophages attack joints and they produce inflammatory mediators that basically sustain inflammation in joints."
The researchers discovered during their experiments that knockout mice with a missing Notch pathway in their macrophages were unable to produce certain types of macrophages and have a lesser inflammatory phenotype.
Dr. Hu explains:
"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."
In simple terms, the Notch pathway is vital in order to differentiate and function of inflammatory macrophages, which in turn are vital for human RA pathogenesis.
The researchers cleaned out the specifics of how Notch influences the molecular cascade, which lead to generating inflammatory macrophages in a series of in vitro studies. Another experiment demonstrated that by using GSI-34, a Notch pathway inhibitor currently under development for the treatment of cancer and Alzheimer's, that the drug was able to block the function of macrophages.
According to the researchers, the study offers an insight into how Notch contributes to rheumatoid arthritis pathogenesis, in addition to demonstrating for the first time that GSI-34 could potentially be used to treat RA.
Various companies are currently in the process of developing Notch inhibitors, some of which are already undergoing Phase III trials.
Dr. Hu concludes: "Before this study, the Notch pathway has been implicated mainly in cancer, but in this study we define how it is connected to RA."
Written By Petra Rattue