Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers identify likely causes, treatment strategies for systemic scleroderma

10.10.2013
Using mice, lab-grown cells and clues from a related disorder, Johns Hopkins researchers have greatly increased understanding of the causes of systemic sclerosis, showing that a critical culprit is a defect in the way certain cells communicate with their structural scaffolding.

They say the new insights point the way toward potentially developing drugs for the disease, which affects approximately 100,000 people in the United States.

"Until now we've had little insight and no effective treatment strategies for systemic sclerosis, and many patients die within a year of diagnosis," says Hal Dietz, a professor in the Institute of Genetic Medicine and director of the Smilow Center for Marfan Syndrome Research at Johns Hopkins.

"Our group created mouse models that allowed us to learn about the sequence of events that leads to the disease's symptoms, and we hope drugs can be developed that target one or more of these events." The Dietz team's results are described in the Oct. 10 issue of Nature.

Patients with systemic sclerosis, also known as systemic scleroderma, experience a sudden hardening, or fibrosis, of the skin. For some patients, this hardening occurs only in limited areas, but for others, it quickly spreads across the body and to organs such as the heart, intestines and kidneys. It is this fibrosis of the internal organs that is often fatal.

Systemic sclerosis rarely runs in families, Dietz says, making the gene for the disease, if it exists, very difficult to find. Without a known genetic mutation, researchers had not been able to create a genetically altered mouse with which to study the condition. But Dietz's group was struck by the similarities between systemic sclerosis and a less severe, much rarer condition called stiff skin syndrome (SSS), which does run in families, and they suspected that learning more about SSS would also shed light on systemic sclerosis.

In a previous experiment , they pinpointed the genetic mutation responsible for SSS in a gene for a protein called fibrillin-1, which plays a role in other connective tissue disorders. In certain types of tissues, including skin, fibrillin-1 helps make up the scaffolding for cells. The specific changes in fibrillin-1 seen in SSS patients were predicted to impair the ability of cells to make contact with fibrillin-1 through bridging molecules called integrins.

In the current study, M.D./Ph.D. student Elizabeth Gerber created a line of mice with a genetic variant similar to that found in SSS patients. To test the group's hypothesis, Gerber also created a line of mice with a variant the team knew would prevent fibrillin-1 from interacting with integrin. As the team expected, both groups of mice developed patches of stiff skin, along with elevated levels of proteins and cells involved in the immune response—much like humans with SSS or systemic sclerosis. "It seemed we were right that the SSS mutation causes the condition by blocking fibrillin's interaction with integrin," Dietz says. "Something else we found was that both types of mice had high levels of integrin in their skin, which made us think their cells were trying to compensate for the lack of fibrillin-integrin interaction by making more and more integrin."

This still left open the question of what was ultimately causing fibrosis, however: Was it the integrin levels or the immune response? Dietz's group delved deeper into the question by creating mice that had both the SSS mutation and artificially low levels of integrin, and found that the mice never developed fibrosis or an abnormal immune response. "They looked normal," Dietz says.

The team next tried waiting until mice with the SSS mutation had developed fibrosis, then treating them with a compound known to block a key molecule with known connections to both fibrosis and the immune response. This reversed the mice's skin fibrosis and immunologic abnormalities. The team also tested the compounds on lab-grown human skin cells with systemic sclerosis, with the same results. This raises the possibility that systemic sclerosis patients could eventually be treated with similar compounds in humans, Dietz says. A number of the compounds that proved effective in SSS mice and systemic sclerosis cells are currently being explored by drug companies for the treatment of other conditions, prominently including cancer.

The results raised another big question for the team: Which of the several types of skin cells were responsible for the runaway immune response and fibrosis? They traced the activity to so-called plasmacytoid dendritic cells, or pDCs, a cell type known to either tamp down or ramp up immune response, depending on the circumstances.

"Dietz's work gives scleroderma patients hope that we have gained fundamental insights into the process of fibrosis in scleroderma. In particular, I am confident that within a relatively short time, novel therapies can be tested in patients, and I am optimistic that such treatments will have a profound effect," says Luke Evnin, Ph.D., chairman of the board of directors of the Scleroderma Research Foundation and a scleroderma patient.

Other authors on the study were Elizabeth E. Gerber, Elena M. Gallo, Stefani C. Fontana, Fredrick M. Wigley and David L. Huso, all of the Johns Hopkins University School of Medicine, and Elaine C. Davis of McGill University.

The study was funded by the Scleroderma Research Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers RO1-AR41135 and PO1-AR049698), the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research, and the Howard Hughes Medical Institute.

Shawna Williams | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Health and Medicine:

nachricht Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>