Scientists find new mechanism by which cell signaling pathway contributes to rheumatoid arthritis development

May 20, 2012

A new study led by researchers at Hospital for Special Surgery identifies the mechanism by which a cell signaling pathway contributes to the development of rheumatoid arthritis (RA). In addition, the study provides evidence that drugs under development for diseases such as cancer could potentially be used to treat RA. Rheumatoid arthritis, a systemic inflammatory autoimmune disease that can be crippling, impacts over a million adults in the United States.

"We uncovered a novel mechanism by which the 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. The study appears online in advance of print in Nature Immunology.

Prior to this study, researchers knew that an intracellular molecular pathway called Notch is involved in diseases such as cancer. In the last year, other scientists conducted a genome wide association study to identify genes that were linked to the development of rheumatoid arthritis. They discovered 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 Dr. Hu. Working with researchers at other institutions in the United States and abroad, HSS investigators started putting two and two together and noted that Notch might be involved in a misfiring of the immune system that is commonly seen in RA.

The researchers designed experiments to test whether the Notch pathway had an influence on , a type of white blood cell that is most commonly known for gobbling up but which can also cause inflammation. Macrophages that have gone 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 in joints," said Dr. Hu.

In experiments, researchers found that knockout mice that lack the Notch pathway in macrophages were unable to produce certain type of macrophages and exhibited 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 Dr. Hu. In a nutshell, 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 that leads 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 inhibit the function of macrophages.

The researchers say the study provides the first explanation of how Notch contributes to pathogenesis. It also shows, for the first time, that 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 currently 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," said Dr. Hu.

Explore further: Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis

Related Stories

Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis

May 22, 2011
A new study by rheumatologists at Hospital for Special Surgery in New York has shown that a powerful pro-inflammatory protein, tumor necrosis factor (TNF), can also suppress aspects of inflammation. The researchers say the ...

Study reveals origins of a cancer affecting the blood and bone marrow

May 12, 2011
A new study by the NYU Cancer Institute, an NCI-designated cancer center, sheds light on the origins of myeloid leukemia, a type of blood cancer that affects children and adults. The researchers discovered that novel mutations ...

Gatekeeper signal controls skin inflammation

January 26, 2012
A new study unravels key signals that regulate protective and sometimes pathological inflammation of the skin. The research, published online on January 26th in the journal Immunity by Cell Press, identifies a "gatekeeper" ...

Defect in A20 gene expression causes rheumatoid arthritis

August 16, 2011
Researchers from VIB (Flanders Institute for Biotechnology) and Ghent University have shown that a defective gene can contribute to the onset of rheumatoid arthritis, an often-crippling inflammation of the joints that afflicts ...

Recommended for you

The skinny on lipid immunology

October 20, 2017
Phospholipids - fat molecules that form the membranes found around cells - make up almost half of the dry weight of cells, but when it comes to autoimmune diseases, their role has largely been overlooked. Recent research ...

Bacterial pathogens outwit host immune defences via stealth mechanisms

October 20, 2017
Despite their relatively small genome in comparison to other bacteria, mycoplasmas can cause persistent and often difficult-to-treat infections in humans and animals. An extensive study by researchers from Vetmeduni Vienna ...

Scientists find where HIV 'hides' to evade detection by the immune system

October 19, 2017
In a decades-long game of hide and seek, scientists from Sydney's Westmead Institute for Medical Research have confirmed for the very first time the specific immune memory T-cells where infectious HIV 'hides' in the human ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Researchers release the brakes on the immune system

October 18, 2017
Many tumors possess mechanisms to avoid destruction by the immune system. For instance, they misuse the natural "brakes" in the immune defense mechanism that normally prevent an excessive immune response. Researchers at the ...

How cytoplasmic DNA triggers inflammation in human cells

October 17, 2017
A team led by LMU's Veit Hornung has elucidated the mechanism by which human cells induce inflammation upon detection of cytoplasmic DNA. Notably, the signal network involved differs from that used in the same context in ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.