|
HOUSTON -- (February 24, 2008) -- Notch, a protein known to govern
the determination of cell differentiation into different kinds of
tissues in embryos, plays a critical role in bone formation and
strength later in life, said researchers from Baylor College of
Medicine in Houston in a report that appears online today in the
journal Nature Medicine. Their findings may provide a basis for
understanding osteoporosis and diseases in which there is too much bone.
Two functions of Notch in bone
"We knew that Notch is important in patterning the skeleton," said
Dr. Brendan Lee, professor of molecular and human genetics and
pediatrics at BCM and a Howard Hughes Medical Institute investigator.
"After this initial patterning of the skeleton, we saw a dimorphic or
two-pronged function for Notch. If there was an increase of Notch
activity in bone cells, we get a lot more bone. Notch stimulates early
proliferation of osteoblastic cells (cells responsible for bone
formation). However, when they 'knocked out' the Notch function in such
cells in the laboratory, they found osteoporosis or the loss of bone,
similar to age-related osteoporosis in humans."
"Mice had an acceptable amount of bone at birth, but as they got
older, they lost more and more bone," said Lee, senior author of the
report. "Loss of Notch signaling might relate to what happens when we
get older."
They found that the osteoblasts, which promote bone formation,
worked fine when they abolished Notch function in bone forming cells.
However, the animals lacked the ability to regulate activity of
osteoclasts, whose primary function is to resorb or remove bone. Many
women who have osteoporosis actually have a similar problem, an
imbalance of bone formation vs. bone resorption. They make enough bone
but they resorb bone cells at an abnormally high rate.
In the laboratory, Lee and his colleagues found that when animals
were bred to lack Notch, they lost also the ability to suppress bone
resorption. That balance between bone formation and resorption allows
organisms to maintain a healthy skeleton.
Clinical potential
Future studies may look at the possiblity that loss of Notch
interferes with the natural signal between osteoblasts and osteoclasts
and prevents the homeostasis or natural balance between the two.
That means the protein Notch and the cellular pathways that express
and control it might be targets for drugs to treat bone disorders, said
Lee, also a researcher in the Dan L. Duncan Cancer Center at BCM.
The work demonstrates the importance of going from patients to the
laboratory and back again, he said. This study began with patients who
suffer from a problem called spondylocostal dysplasia. These children
and adults have problems with the pattern of their spine. They have
fusions of parts of the spine or ribs. Several years ago, other
scientists showed that a mutation of the pathway for Notch causes some
of these problems. "Our care of these patients suggested to us that
Notch may have important function even after the establishment of this
initial pattern of the skeleton."
Other roles for Notch
Notch also plays a role in other disorders, including those of the blood and cancer.
"Notch is important in the blood system," said Lee. "It regulates
whether a stem cell becomes a 'T' or a 'B' cell. When Notch is mutated
in the blood system, it causes cancer."
That knowledge led him and his colleagues to look at the protein in bone.
"This is a complex system and it is why personalized medicine is
important," said Lee. "By identifying all of the major (cellular)
pathways that contribute to a specific trait or feature like bone mass
in each person, we could one day develop therapies specific for that
person."
Others who took part in this work include Feyza Engin, Tao Yang,
Guang Zhou, Terry Bertin, Ming Ming Jiang, Yuqing Chen, Lisa Wang, Hui
Zheng and Richard E. Sutton, all of BCM, and Zhenqiang Yao and Brendan
F. Boyce at the University of Rochester Medical Center in New York.
Funding for this work came from the National Institutes of Health. The article can be found at http://www.nature.com/nm/index.html.
Powered by AkoComment 2.0! |
