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 New Technique Maps Elusive Chemical Markers on Proteins
03.07.2015 | Salk Institute for Biological Studies

nachricht New approach to targeted cancer therapy
03.07.2015 | CECAD - Cluster of Excellence at the University of Cologne

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Viaducts with wind turbines, the new renewable energy source

Wind turbines could be installed under some of the biggest bridges on the road network to produce electricity. So it is confirmed by calculations carried out by a European researchers team, that have taken a viaduct in the Canary Islands as a reference. This concept could be applied in heavily built-up territories or natural areas with new constructions limitations.

The Juncal Viaduct, in Gran Canaria, has served as a reference for Spanish and British researchers to verify that the wind blowing between the pillars on this...

Im Focus: X-rays and electrons join forces to map catalytic reactions in real-time

New technique combines electron microscopy and synchrotron X-rays to track chemical reactions under real operating conditions

A new technique pioneered at the U.S. Department of Energy's Brookhaven National Laboratory reveals atomic-scale changes during catalytic reactions in real...

Im Focus: Iron: A biological element?

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and a half billion years ago.

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and...

Im Focus: Thousands of Droplets for Diagnostics

Researchers develop new method enabling DNA molecules to be counted in just 30 minutes

A team of scientists including PhD student Friedrich Schuler from the Laboratory of MEMS Applications at the Department of Microsystems Engineering (IMTEK) of...

Im Focus: Bionic eye clinical trial results show long-term safety, efficacy vision-restoring implant

Patients using Argus II experienced significant improvement in visual function and quality of life

The three-year clinical trial results of the retinal implant popularly known as the "bionic eye," have proven the long-term efficacy, safety and reliability of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference on Regenerative Medicine in Leipzig: Last chance to submit abstracts until 2 July

25.06.2015 | Event News

World Conference on Regenerative Medicine: Abstract Submission has been extended to 24 June

16.06.2015 | Event News

MUSE hosting Europe’s largest science communication conference

11.06.2015 | Event News

 
Latest News

Siemens receives order for offshore wind power plant in Great Britain

03.07.2015 | Press release

'Déjà vu all over again:' Research shows 'mulch fungus' causes turfgrass disease

03.07.2015 | Agricultural and Forestry Science

Discovery points to a new path toward a universal flu vaccine

03.07.2015 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>