Researchers from the Hospital for Special Surgery (HSS) in New York City have found that a cell-to-cell communication pathway called the Notch pathway may contribute to the development of rheumatoid arthritis.
According to the study authors, the findings suggest that drugs currently under development for the treatment of other diseases like cancer and Alzheimer’s may also help treat rheumatoid arthritis.
Millions of Americans suffer from rheumatoid arthritis, an autoimmune disease that leads the immune system to essentially attacks its own joints, causing inflammation and pain. Previous studies had associated a certain mutation in a gene involved in the Notch pathway with a higher risk of rheumatoid arthritis, but it wasn’t clear why, so the researchers at HSS sought to figure out whether this molecular pathway played any role in the immune system failures that cause arthritis.
The researchers looked specifically at how the Notch pathway influenced the development of macrophages, a type of immune cell that usually attacks invading pathogens. When macrophage development goes wrong, however, the cells can cause widespread inflammation and destruction — attacking joints and contributing to rheumatoid arthritis.
“In general, macrophages are thought to play a pathogenic role in rheumatoid arthritis by secreting inflammatory mediators that contribute to joint inflammation and bone erosion. A subtype of macrophages named inflammatory macrophages is particularly bad, as they specialize in producing large amounts of inflammatory mediators,” says lead researcher Dr. Xiaoyu Hu, a research scientist at HSS.
A cell receives signals from its neighbors through the Notch pathway, and responds to such signals with certain behavior changes, such as regulation of its own gene expression. The researchers focused on the way the pathway affected the macrophage differentiation. In experiments using knockout mice that had been genetically engineered to lack the Notch pathway in macrophages, the researchers found that animals were unable to produce inflammatory macrophages, which served to reduce inflammation overall.
Previously, the Notch pathway has been studied mainly for its involvement in other diseases. Indeed, experimental Notch-inhibiting drugs are currently being tested for the treatment of cancer and Alzheimer’s — two conditions that also involve inflammation. The authors of the current study suggest these compounds might prove helpful for rheumatoid arthritis as well. In lab studies, Hu and her colleagues tested an experimental Notch inhibitor called GSI-34 and found that the drug inhibited macrophage function.
In a phase III trial for Alzheimer’s disease, however, another Notch inhibitor — LY450139 developed by Eli Lilly — that affects gamma-secretase, an enzyme involved in Notch signaling, was proven ineffective. There are currently other gamma-secretase inhibitors in phase II trials for various cancers, but there have been no trials of Notch inhibitors on inflammatory diseases like rheumatoid arthritis, according to Hu.
“Despite all the research effort, it is still not clear exactly what causes joint inflammation — a very complex process influenced by a number of genetic and environmental factors. Macrophages clearly contribute to joint inflammation and targeting inflammatory macrophages may represent a promising therapeutic approach to dampen joint inflammation,” says Hu.
Hu says the next step in the research will be to measure the involvement of the Notch pathway in animal models of rheumatoid arthritis and to evaluate the efficacy of Notch inhibitors in treating arthritis in animals.
The study was published online by Nature Immunology.