In their study, the scientists discovered that blocking the function of a particular molecule in the ear bone of mice decreased the hardness of the bone, causing hearing loss. Reactivating the molecule restored the bone’s hardness – and the animals’ hearing.
The research likely explains the previously unknown cause of hearing loss in the human disease cleidocranial dysplasia, a genetic bone syndrome,said co-author Lawrence Lustig, MD, UCSF professor of otolaryngology, and may explain hearing loss associated with some other bone diseases.
More broadly, the finding reveals the molecular pathway that regulates the physical properties of extracellular matrix – the interlocking mesh of molecules between cells – in the ear’s cochlear bone. The matrix is responsible for the hardness of human tissues, ranging from stiff bone and enamel to compliant brain and skin.
Perhaps most intriguing is the discovery that variations in the physical properties of extracellular matrix affect tissue function. This finding should lead to insights into abnormal matrix properties in the tissues of diseases throughout the body, the researchers said, including osteoporosis and arthritis.
The polar bear’s ear bone is believed to be the hardest in its body, possibly helping the animal hear under water.
“Our finding demonstrates that establishing and maintaining the proper calibration of physical properties is essential for healthy tissue function,” said the senior author of the study, Tamara Alliston, PhD, assistant professor of orthopaedic surgery and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
Scientists have known that physical cues, such as extracellular matrix stiffness, direct the differentiation of stem cells into specific cell types, such as heart, liver and brain cells. They also have known that disruption of these cues underlies a wide range of diseases, such as osteoarthritis, cardiovascular disease and cancer.
However, they have not known the molecular mechanisms that establish the physical properties of extracellular matrix, nor the link between these properties and tissue function.
In the current study, recently reported in EMBO (online Sept. 17, 2010), the team, led by Jolie L. Chang, MD, a resident in the UCSF Department of Otolaryngology and Head and Neck Surgery, set out to investigate the mechanisms involved.
Earlier studies, conducted at UCSF, showed that a molecule known as transforming growth factor beta (TGF-â) regulates the turnover of bone cells known as osteoblasts, by inhibiting a molecule known as Runx2. Disrupting TGF-â’s regulation of Runx2 causes dysplastic clavicles and open cranial sutures.
These skeletal deformities, seen in the human genetic bone disease cleidocranial dysplasia, result from a defective copy of the Runx2 gene. Patients with CCD experience “sensorineural” hearing loss – caused by damage to the cochlear bone or nerve damage.
Given these conditions, the teams used two mouse models of CCD to study the regulation and role of bone matrix properties in the cochlear bone.
They focused on this bone in part because of anecdotal evidence in patients, and research in whales, flamingos and polar bears, indicating that the bone is the hardest in the body, in the case of whales possibly helping the animals hear under water. The required stiffness, the team suspected, likely would be precisely calibrated.
They first conducted a nanoscale analysis of several mouse bones in the head and ear, establishing that the cochlea bone was by far the stiffest.
Then, in what they considered a major insight, they discovered that TGF-â regulates Runx2 to establish the physical property of the extracellular matrix of the cochlea bone. “This told us,” said Chang, “that Runx2—a key transcriptional regulator that helps the cell select its cell fate—also controls the physical properties of the matrix.”
Finally, by manipulating Runx2 activity through TGF-â, the team determined that the physical quality of the bone matrix affects hearing.
Now, the team is investigating the molecules “downstream” of Runx2, to gain further insight into the mechanism regulating the physical properties of bone. They also are studying if these mechanisms define the stiffness of matrices in other skeletal tissues.
“We want to see if TGF-â targets the cartilage transcription factor to make cartilage more or less stiff,” Alliston said. “We think that the stiffness is degraded in arthritis and that this further disrupts chondrocyte cells, exacerbating the disease.”
Other co-authors of the study are Delia S. Brauer, Jacob Johnson, Carol Chen, Omar Akil, Emily N. Chin, Kristen Butcher, Richard A. Schneider, Anil Lalwani, Rik Derynck, Grayson W. Marshall, and Sally J. Marshall, of UCSF, Guive Balooch, at the time a postdoctoral fellow in the lab of co-author Robert O. Ritchie, of UC Lawrence Berkeley National Laboratories, Mary Beth Humphrey, of University of Oklahoma Health Science Center, and Alexandra E Porter, of Imperial College London.
The study was funded primarily by the National Institutes of Health, the Deafness Research Foundation, The Arthritis Foundation, UCSF School of Dentistry Creativity Fund, Arthritis Foundation, Deafness Research Foundation and Department of Energy.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Jennifer O'Brien | EurekAlert!
Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung
Scientists reveal source of human heartbeat in 3-D
07.08.2017 | University of Manchester
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences