Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Bone quality regulator identified, suggests drug target


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:

More articles from Life Sciences:

nachricht Strong, steady forces at work during cell division
20.10.2016 | University of Massachusetts at Amherst

nachricht Disturbance wanted
20.10.2016 | Max Delbrück Center for Molecular Medicine in the Helmholtz Association

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Innovative technique for shaping light could solve bandwidth crunch

20.10.2016 | Physics and Astronomy

Finding the lightest superdeformed triaxial atomic nucleus

20.10.2016 | Physics and Astronomy

NASA's MAVEN mission observes ups and downs of water escape from Mars

20.10.2016 | Physics and Astronomy

More VideoLinks >>>