Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Novel treatment strengthens bones in genetic disease

15.08.2014

An enzyme therapy may prevent skeletal abnormalities associated with the genetic disorder neurofibromatosis type-1, Vanderbilt investigators have discovered.

The researchers demonstrated in a mouse model of the disorder that the enzyme asfotase-alpha improves bone growth, mineralization and strength. The findings, reported in the journal Nature Medicine, “suggest that we can make bone stronger and better by injecting this drug, and possibly prevent fractures in patients with neurofibromatosis,” said Florent Elefteriou, Ph.D., director of the Vanderbilt Center for Bone Biology.


Mice missing the gene neurofibromin in bone cells have more non-calcified bone (osteoid), shown in pink, compared to normal mice. In this image, calcified bone is black and bone-forming osteoblasts lining the deposited osteoid are orange-brown.

While he is excited about the results, Elefteriou emphasized the challenge of moving from mouse to human studies. “It’s very difficult to set up a clinical trial in patients with a rare disease; it will have to be an international effort to pool these patients,” he said.

Neurofibromatosis type-1 (NF1) is caused by mutations in the gene for neurofibromin, a protein that regulates cellular signaling pathways. The disorder causes nervous system tumors and skeletal pathologies including scoliosis, bone fragility, fracture and pseudoarthrosis (non-union of the bone following fracture).

Fractures are treated surgically to stabilize the bone and promote healing. Some families opt for amputation, to spare their children the pain of repeated surgeries, Elefteriou said.

“We wondered if there might be a way to prevent the fractures from happening in the first place,” he said.

It was difficult to even propose non-surgical preventive treatments, however, because it was unclear how mutations in neurofibromin cause skeletal pathologies.

To investigate the molecular pathology of NF1, Elefteriou and his colleagues, including first author Jean de la Croix Ndong, Ph.D., have studied a mouse model of the disorder. They noticed in histological stains of bone tissue that the mice had an accumulation of non-mineralized matrix, a condition called hyperosteoidosis.

They have now discovered that hyperosteoidosis in the mice is caused by accumulation of the molecule pyrophosphate, a strong inhibitor of bone mineralization. They found that in the absence of neurofibromin, the expression of certain genes is upregulated. These include genes that enable increased production and transport of pyrophosphate and a gene that prevents calcium and phosphate from depositing on collagen fibers.

In addition, the bone-forming cells fail to differentiate (mature) into “proper tenure-track osteoblasts,” Elefteriou said, which means the cells don’t produce alkaline phosphatase, the enzyme that normally breaks down pyrophosphate.

“That’s a fourth factor preventing mineralization and the formation of new good bone,” he said.

The investigators decided to try clearing the accumulated pyrophosphate by treating the mice with asfotase-alpha, an engineered form of alkaline phosphatase. Asfotase-alpha is currently in clinical trials for hypophosphatasia, another rare genetic disease affecting bone formation.

They found that asfotase-alpha treatment improved bone mass, mineralization and bone mechanical properties in the mouse model of NF1.

“This could be a drug that would prevent fractures and help these kids pass through the early rapid growth period and reach the point where they aren’t as likely to fracture the bone,” Elefteriou said.

To explore whether the molecular pathology of the disease is the same in humans as in the mouse model, the researchers studied pseudoarthrosis tissue biopsies from patients with NF1. They found that the gene that promotes pyrophosphate synthesis is upregulated, suggesting a similar molecular pathology and supporting the notion that asfotase-alpha may be a successful treatment in patients.

There’s much work to be done first, Elefteriou cautions. He notes that although the enzyme therapy corrects the functional defect of pyrophosphate accumulation, it does not correct the failure of osteoblasts to differentiate. This may indicate a need for long-term and combination drug therapy, which the researchers will examine in the mouse model.

They will also continue to collaborate with members of the Children’s Tumor Foundation Bone Consortium to develop clinical trials.

“I think we’ve made great progress in this area,” Elefteriou said. “It’s exciting that instead of fixing the bones after they break, we might have a drug now to prevent the fractures.”

Other Vanderbilt Center for Bone Biology contributors to the studies included Alexander Makowski, Sasidhar Uppuganti, Guillaume Vignaux, Ph.D., Koichiro Ono, Ph.D., Daniel Perrien, Ph.D., and Jeffry Nyman, Ph.D. Additional contributors included Simon Joubert, Ph.D., at Alexion Pharmaceuticals, Serena Baglio, Ph.D., and Donatella Granchi, Ph.D., at Istituto Ortopedico Rizzoli in Bologna, Italy, David Stevenson, M.D., at the University of Utah and Jonathan Rios, Ph.D., at University of Texas Southwestern Medical Center.

This research was supported by a Young Investigator Award from the Children’s Tumor Foundation and by grants from the National Institutes of Health (AR055966, RR027631, TR001105).

Contact:
Leigh MacMillan, (615) 322-4747
leigh.macmillan@vanderbilt.edu

Leigh MacMillan | Eurek Alert!
Further information:
http://news.vanderbilt.edu/2014/08/novel-treatment-strengthens-bones-in-genetic-disease/

Further reports about: Biology Foundation Medicine NF1 Nature Tumor Vanderbilt disorder enzyme genes

More articles from Life Sciences:

nachricht Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University

nachricht Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017
25.04.2017 | Laser Zentrum Hannover e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA examines newly formed Tropical Depression 3W in 3-D

26.04.2017 | Earth Sciences

New High-Performance Center Translational Medical Engineering

26.04.2017 | Health and Medicine

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>