Scientists identify new target to battle rheumatoid arthritis
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 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. 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 macrophages, a type of white blood cell that is most commonly known for gobbling up pathogens 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 inflammation 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.
Risk factors for the development of rheumatoid arthritis
There is increasing interest in attempting to understand what the risk factors are that lead to the development of rheumatoid arthritis (RA). Twin studies have proved a genetic role but also quantified the non-genetic risk. There is thus scope for identifying environmental predictors that might offer a strategy to prevent the disease. Changes in the female hormonal environment such as in pregnancy, breastfeeding and the use of the oral contraceptive (OC) pill appear to have a role. Of the traditional lifestyle exposures, cigarette smoking has been associated with a consistently increased risk that might also apply to the passive inhalation of smoke. Occupation probably has a minor influence, although exposure to silica dust is of aetiological importance. Recent studies have highlighted a role for diet, with suggestions that diets high in caffeine, low in antioxidants and high in red meat may contribute to an increased risk. The most plausible environmental exposure is infection and although several decades of study have produced few definitive candidate organisms, Epstein-Barr virus (EBV) remains an interesting target.
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PMID: 16766362 [PubMed - indexed for MEDLINE]
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Oliver JE, Silman AJ.
Source: arc Epidemiology Unit, Manchester University, School of Epidemiology and Health Sciences, Manchester, UK
“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.
New Genetic Clue in Development of Rheumatoid Arthritis
cientists at Mount Sinai Hospital, in collaboration with researchers at the University of Toronto, University Health Network and McGill University have obtained significant new insights into the causes of rheumatoid arthritis (RA) and other autoimmune disorders including type 1 diabetes, lupus and Graves disease.
The findings represent a key initial step in realizing the full potential of genomics and personalized medicine.
In a study published online in Nature Genetics on August 14, Dr. Katherine Siminovitch and her team identified the exact means by which an alteration in the gene PTPN22 increases risk for RA and other autoimmune disorders.
The study used advanced genomics technologies that enable testing of millions of genetic markers in a single experiment to identify genes, such as PTPN22, that confer risk for disease.
The team then generated a mouse genetic model to show how the PTPN22 gene mutation impairs immune cell function and then validating their findings in humans, taking their discovery from the laboratory bench to the clinic.
The result: a more accurate understanding of how autoimmune conditions develop, and how new diagnostic tests and targeted therapies can be designed for better symptom control and potential cure.
“Our findings are particularly exciting because this study sets a new precedent for studying arthritis and other autoimmune disorders,” said lead author Dr. Siminovitch, Senior Investigator and the Sherman Family Research Chair in Genomic Medicine at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, a professor at the University of Toronto, and Director of the Fred A. Litwin & Family Centre in Genetic Medicine.
The researchers say the study provides the first explanation of how Notch contributes to rheumatoid arthritis 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.
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The study was supported by funding from the National Institutes of Health and the American College of Rheumatology. Other authors involved in the study include Hospital for Special Surgery researchers Baohong Zao, Ph.D., Lionel Ivashkiv, M.D., Carl Blobel, M.D., Ph.D., Jimmy Zhu, Sinead Smith, and Allen Chung; Julia Foldi, Ph.D., and Chao Shi, Ph.D., from Weill Cornell Graduate School of Medical Sciences; Hasina Outtz and Jan Kitajewski, Ph.D., from Columbia University; Silvio Weber and Paul Saftig, Ph.D., from the Christian Albrechts Universitat Kiel, Kiel, Germany; Yueming Li, Ph.D., from Memorial Sloan-Kettering Cancer Center; and Keiko Ozato, Ph.D., from the National Institute of Child Health and Human Development.
About Hospital for Special Surgery
Founded in 1863, Hospital for Special Surgery (HSS) is a world leader in orthopedics, rheumatology and rehabilitation. HSS is nationally ranked No. 1 in orthopedics, No. 2 in rheumatology, No. 19 in neurology, and No. 16 in geriatrics by U.S.News & World Report (2011-12), and is the first hospital in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center three consecutive times. HSS has one of the lowest infection rates in the country. From 2007 to 2011, HSS has been a recipient of the HealthGrades Joint Replacement Excellence Award. HSS is a member of the NewYork-Presbyterian Healthcare System and an affiliate of Weill Cornell Medical College and as such all Hospital for Special Surgery medical staff are faculty of Weill Cornell. The hospital’s research division is internationally recognized as a leader in the investigation of musculoskeletal and autoimmune diseases.
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Phyllis Fisher
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