Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Bone quality regulator identified, suggests drug target

14.12.2005


UCSF scientists have determined that the quality of bone matrix, a key component of bone, is regulated by a molecule known as transforming growth factor beta. The finding, they say, suggests a possible target for preventing and treating bone fractures associated with aging and genetic diseases.



The study will be reported later this week in the Online Early Edition of Proceedings of the National Academy of Sciences (PNAS).

The ability of bone to resist damage depends on the mass, or quantity, of bone, its architecture and the quality of bone matrix, the mineralized material between cells.


Several molecular factors have been shown to regulate the mass and architecture of bone. So far, however, none have been shown to regulate bone matrix, which is responsible for bone elasticity and toughness.

There has been significant disagreement about whether the quality of bone matrix varies among individuals and, if it does, whether it could be altered for therapeutic reasons. In any case, until now, scientists have lacked a strategy for measuring its quality and teasing out its impact, says senior study author Tamara Alliston, PhD, UCSF assistant adjunct professor of Cell and Tissue Biology.

In the current study, the team explored whether transforming growth factor beta (TGF-ß) regulates the properties of bone matrix because there were hints that it might. TGF-ß is known to play a role in the development of osteoblasts, cells that produce bone matrix.

The researchers carried out their evaluation in five sets of mice genetically engineered to produce differing levels of TGF-ß signaling within osteoblasts, and, for comparison, in normal, or ’wild type’ mice. After the animals had been euthanized, the team utilized highly sensitive instruments developed in the materials sciences -- atomic-force microscopy, x-ray tomography and micro-Raman spectroscopy -- to measure the properties of bone matrix independent of bone mass and architecture. They also compared the bones’ resistance to fracture in a bending test.

The results were notable, according to Alliston. In animals genetically engineered to produce high levels of TGF-ß, the measurements of bone matrix indicated increased susceptibility to fracture. The matrix was less elastic, less hard and contained lower levels of the mineral calcium phosphate. In addition, the animals’ bones were less resistant to fracture in the bending test.

In contrast, in animals with low levels of TGF-ß the bone matrix was more elastic, harder, had higher mineral concentration and the bone overall had increased mass. In addition, the bones were more resistant to fracture in the bending test.

The bones studied included the femur, tibia and calvarial parietal bones.

"This is the first evidence that properties of bone matrix can be regulated by a growth factor and that by modifying the TGF-ß pathway, specifically, these properties can be controlled," says Alliston.

The study suggests, she says, that TGF-ß could be targeted for clinical intervention in patients. "By decreasing TGF-ß signaling at the relevant site in the body, we may be able to improve the quality of bone to either prevent the damage that occurs in osteoarthritis and osteoporosis, or improve the quality and speed of bone repair following bone fracture, joint implantation, dental implants or bone grafting.

Aging baby boomers

This strategy could prove particularly useful for aging baby boomers, as joint-replacement therapy often fails over the course of years, says Alliston. Hip replacements, for example, often fail within 15 years, and a second replacement takes a significant toll on the body. A person receiving a hip replacement at age 55 or 60 generally will require a second one by age 70.

"If we could decrease the production of TGF-ß at the site of the transplant, we might be able to strengthen the quality of bone being formed," says the lead author of the study, Guive Balooch, BA, in the UCSF Graduate Program in Oral and Craniofacial Sciences and Division of Bioengineering.

Of note, clinical trials are being developed to test whether a drug that inhibits TGF-ß will prevent cancers from metastasizing in patients, says co-senior author Rik Derynck, PhD, director of the UCSF Program in Craniofacial and Mesenchymal Biology, UCSF Department of Cell and Tissue Biology, and co-director of the UCSF Institute of Stem Cell and Tissue Biology. This separate line of investigation involving TGF-ß builds on evidence that cancer cells "up regulate" or increase, TGF-ß when they decide to metastasize. Scientists hypothesize that the increased levels of TGF-ß enhance the ability of cancer cells to invade other tissues.

Such a drug could also prove useful in modifying bone quality. It could even prove useful in treating the bone deterioration that often occurs when cancers metastasize to the bone, he says.

It is worth noting that the findings do not detract from the theory that bone mass, or quantity, is an important determinant of bones’ ability to withstand fracture, says Alliston. One set of genetically engineered mice in the study had higher quality of bone matrix and lower bone mass -- and the bone fractured more easily.

The overall finding, she says, was that a reduction in TGF-ß signaling enhanced the quality of bone matrix, as well as the bone mass, collectively enabling the bone to better resist fracture.

The team is now exploring the functional significance of the bone matrix properties. "We have identified several factors we think are important, and are in the process of defining their contribution to fracture-resistance," she says.

Risk of bone fractures

Susceptibility to bone fractures and bone deterioration increases with age, often due to metabolic changes. Significant bone loss is diagnosed as osteoporosis. Deterioration in the bone and cartilage of joints is known as osteoarthritis.

Some diseases of bone degeneration are genetic, such as osteogenesis imperfecta, which is characterized by brittleness of bone, rather than loss of bone, and osteopetrosis, in which bones become overly dense, leading to a variety of significant disorders, including blindness, deafness, pathological fractures, and infections.

The new finding offers provocative hints that defects in TGF-ß signaling could play a role in some genetic diseases. Building on ongoing work in the lab, the team is now exploring strategies that could lead them toward TGF-ß’s mechanism of action.

Jennifer O’Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Mass spectrometry sheds new light on thallium poisoning cold case
14.12.2018 | University of Maryland

nachricht Protein involved in nematode stress response identified
14.12.2018 | University of Illinois College of Agricultural, Consumer and Environmental Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Data use draining your battery? Tiny device to speed up memory while also saving power

14.12.2018 | Power and Electrical Engineering

Tangled magnetic fields power cosmic particle accelerators

14.12.2018 | Physics and Astronomy

In search of missing worlds, Hubble finds a fast evaporating exoplanet

14.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>