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 :

» Systemic Sclerosis Patients Treated With Oral Treprostinil Diethanolamine

Patients with effectively absorbed oral treprostinil diethanolamine, which produced a temporal association with improved cutaneous perfusion and temperature, according to study results. In a dual-center, open-label, phase 1 study, researchers...

» Dealing With Joint Pain

In a , Dr. Peter Got noted that the common causes of joint pain include autoimmune disorders, lupus, of the bone, , (that can lead to muscle aches, tenderness and stiffness in the shoulders and hips), gout, , bone cancer, , psoriatic arthritis, ,...

» Endothelin Antagonists Present Great Promise

One of the most intriguing developments in recent medical science is the discovery of the human chemical endothelin (ET). Since its detection in 1988, over 22,000 scholarly articles (about 3 per day) have been published on the subject, a new class...

» TLR4 Protein Implicated In The Fibrosis Associated With Scleroderma

An international multi-disciplinary research team led by scientists has uncovered a new role for the protein toll-like receptor 4 (TLR4) in the development of tissue fibrosis, or scarring.Recently reported in the , this finding has implications for...

» Italians Explain Low Sex Drive In Female Scleroderma Patients

In a world first, Italian rheumatologists have discovered why women living with Systemic Sclerosis often suffer from a low sex drive. The study of 22 women with systemic sclerosis found the disease resulted in a lack of blood flow around the...

» Studies Show That Natural Probiotic Supplements Can Help Reduce and Treat Autoimmune Disease Symptoms

Most consumers are familiar with the dangers of disease-causing bacteria; but over the last several decades, medical professionals and lay consumers alike have discovered a host of proven and potential benefits to be had from the consumption of...