New Target Indentified In The Battle Against Rheumatoid Arthritis Identified PDF Print E-mail
Wednesday, 23 May 2012 05:44
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.

Source: ZeeNews (2012)
 
More articles :

» Toll-like receptor 7 (TLR7)–Driven Accumulation of a Novel CD11c+ B-cell Population is Important for the Development of Autoimmunity

Anatoly V. Rubtsov, Kira Rubtsova, Aryeh Fischer, Richard T. Meehan, Joann Z. Gillis, John W. Kapple, and Philippa MarrackThe American Society of HematologyFemales are more susceptible than males to many autoimmune diseases. The processes causing...

» Autoimmune Disease Symptoms To Look Out For

We have understood for  a long time that the detection and subsequent diagnoses of autoimmune diseases are difficult. However, there are key rheumatic and physical indicators such as joint pain and fatigue, fevers, increasing skin conditions,...

» Liver Autoantibodies in Patients with Scleroderma

Thelma L. Skare & Renato M. Nisihara & Osvaldo Haider & Pedro M. Azevedo & Shirley R. R. UtiyamaClin RheumatolDOI 10.1007/s10067-010-1586-0Association between autoimmune liver diseases and scleroderma has been described. The purpose...

» The Dendritic Cell and The Link between Atherosclerosis and Autoimmunity

Individuals who suffer from autoimmune diseases also display a tendency to develop – the condition popularly known as hardening of the arteries. Clinical researchers at LMU, in collaboration with colleagues in Würzburg, have now discovered a...

» Stanford Medical Researchers Discover Master Regulator of Skin Development

The surface of your skin, called the , is a complex mixture of many different cell types — each with a very specific job. The production, or differentiation, of such a sophisticated tissue requires an immense amount of coordination at the cellular...

» Liver Autoantibodies in Patients with Scleroderma

Thelma L. Skare & Renato M. Nisihara & Osvaldo Haider & Pedro M. Azevedo & Shirley R. R. UtiyamaReceived: 5 January 2010 / Revised: 13 August 2010 / Accepted: 26 September 2010# Clinical Rheumatology 2010Association between...