Notch controls bone formation and strength

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 in diseases in which there is too much 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.

Future studies may look at the possiblity that loss of Notch interferes with the natural signal between osteoblasts and osteoclasts (bone resorbing cells) 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."

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."
-end-
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. After the embargo lifts, the article can be found at http://www.nature.com/nm/index.html.

Baylor College of Medicine

Related Osteoporosis Articles from Brightsurf:

New opportunities for detecting osteoporosis
Osteoporosis can be detected through low dose computed tomography (LDCT) imaging tests performed for lung cancer screening or other purposes.

Oxytocin can help prevent osteoporosis
In a laboratory experiment with rats, Brazilian researchers succeeded in reversing natural processes associated with aging that lead to loss of bone density and strength.

New strategy against osteoporosis
An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

New review on management of osteoporosis in premenopausal women
An IOF and ECTS Working Group have published an updated review of literature published after 2017 on premenopausal osteoporosis.

Cardiac CT can double as osteoporosis test
Cardiac CT exams performed to assess heart health also provide an effective way to screen for osteoporosis, potentially speeding treatment to the previously undiagnosed, according to a new study.

Osteoporosis treatment may also protect against pneumonia
A recent study published in the Journal of Bone and Mineral Research found that nitrogen-containing bisphosphonates (N-BPs) such as alendronate, which are widely used to treat postmenopausal osteoporosis, are linked with lower risks of pneumonia and of dying from pneumonia.

New pharmaceutical target reverses osteoporosis in mice
Biomedical engineers at Duke University have discovered that an adenosine receptor called A2B can be pharmaceutically activated to reverse bone degradation caused by osteoporosis in mouse models of the disease.

A link between mitochondrial damage and osteoporosis
In healthy people, a tightly controlled process balances out the activity of osteoblasts, which build bone, and osteoclasts, which break it down.

Many stroke patients not screened for osteoporosis, despite known risks
Many stroke survivors have an increased risk of osteoporosis, falls or breaks when compared to healthy people.

Many postmenopausal women do not receive treatment for osteoporosis
The benefits of treating osteoporosis in postmenopausal women outweigh the perceived risks, according to a Clinical Practice Guideline issued today by the Endocrine Society.

Read More: Osteoporosis News and Osteoporosis Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.