Notch plays role in formation of strong bone

By Ruth SoRelle, M.P.H.

Scientists already knew that the protein Notch plays a role in how cells differentiate into different tissues in an embryo. However, researchers at Baylor College of Medicine have now determined that it also is important in the formation of bone and in the strength of that bone later in life.

The report appears in a recent issue of the journal Nature Medicine. The finding may have implications for understanding and treating bone disorders such as osteoporosis or those in which too much bone is made.

Skeletal patterning

"We knew that Notch is important in patterning the skeleton," said Brendan Lee, M.D., Ph.D., 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."

Too much bone resorption

"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.

Targeting Notch in treatment

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."

Important to blood system

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.