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.
"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 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.
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. Hospital for Special Surgery is located in New York City and online at www.hss.edu.For more information contact:
Phyllis Fisher | EurekAlert!
Drought hits rivers first and more strongly than agriculture
06.09.2018 | Max-Planck-Institut für Biogeochemie
Landslides triggered by human activity on the rise
23.08.2018 | European Geosciences Union
Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz (Germany) together with scientists from Dresden, Leipzig, Sofia (Bulgaria) and Madrid (Spain) have now developed and characterized a novel, metal-organic material which displays electrical properties mimicking those of highly crystalline silicon. The material which can easily be fabricated at room temperature could serve as a replacement for expensive conventional inorganic materials used in optoelectronics.
Silicon, a so called semiconductor, is currently widely employed for the development of components such as solar cells, LEDs or computer chips. High purity...
Augsburg chemists present a new technology for compressing, storing and transporting highly volatile gases in porous frameworks/New prospects for gas-powered vehicles
Storage of highly volatile gases has always been a major technological challenge, not least for use in the automotive sector, for, for example, methane or...
When we put water in a freezer, water molecules crystallize and form ice. This change from one phase of matter to another is called a phase transition. While this transition, and countless others that occur in nature, typically takes place at the same fixed conditions, such as the freezing point, one can ask how it can be influenced in a controlled way.
We are all familiar with such control of the freezing transition, as it is an essential ingredient in the art of making a sorbet or a slushy. To make a cold...
Thin organic layers provide machines and equipment with new functions. They enable, for example, tiny energy recuperators. In future, these will be installed...
Das Zusammenspiel aus Struktur und Dynamik bestimmt die Funktion von Proteinen, den molekularen Werkzeugen der Zelle. Durch Fortschritte in der...
17.10.2018 | Event News
16.10.2018 | Event News
02.10.2018 | Event News
19.10.2018 | Life Sciences
19.10.2018 | Physics and Astronomy
19.10.2018 | Trade Fair News