HARVARD GAZETTE ARCHIVES

Harvard researchers including Marc Wein (left) and Dallas Jones have identified a protein that helps regulate bone growth and may lead to new drug targets to fight osteoporosis. (Staff photo Stephanie Mitchell/Harvard News Office)

Harvard researchers have identified a protein that helps regulate bone growth and may lead to new drug targets to fight osteoporosis, the bone loss condition that the National Institutes of Health terms "a major public health threat" to more than half of people age 50 or older.

The research, conducted by scientists at the Harvard School of Public Health and Harvard Medical School, identified a protein in mice called Schnurri-3 that when absent results in dramatic increases in bone mass.

The work was led by research associate in the School of Public Health's Department of Immunology and Infectious Diseases Dallas Jones, M.D./Ph.D. student Marc Wein, and Irene Heinz Given Professor of Immunology and Professor of Medicine Laurie Glimcher. It was published in the May 26 issue of the journal Science.

The researchers were examining mouse bone marrow while doing work on the immune system when they came upon a surprise. Mice lacking the gene that creates the Schnurri-3 protein, previously thought to be important in the immune system, had a dramatic increase in bone mass. Realizing the importance of bone growth for diseases such as osteoporosis, they explored how Schnurri-3 operated.

They discovered that the Schnurri-3 protein works with another enzyme called WWP1 to restrict the activity of bone-forming cells called osteoblasts. When the Schnurri-3 protein was present, bone growth was normal, but when removed, experimental mice grew bones that were denser.

Despite the differences between mice and humans, mice are susceptible to the same age-related bone loss as humans, Wein said, and older mice lacking the Schnurri-3 protein maintained a robust skeleton.

"They're resistant to age-related bone loss," Wein said.

Researchers realized that if the effect could be repeated in humans, they might have hit upon a new way to attack bone loss due to osteoporosis or cancer.

Osteoporosis is a major health problem for older people, afflicting an estimated 10 million Americans. Another 34 million have low bone mass, putting them at risk for developing osteoporosis. Of the 44 million threatened by the disease, 80 percent are women.

Osteoporosis is thought to be responsible for an estimated 1.5 million fractures each year, costing an estimated $47 million each day to treat. Over 700,000 of those fractures are of the vertebrae and over 300,000 are of the hip. Twenty-four percent of patients over age 50 suffering from hip fractures die in the year following their fracture and 25 percent need long-term care afterward.

Though researchers knew that interfering with Schnurri-3's effects could prove beneficial as a way to fight bone loss, they also realized that the best way to do that was not to attack the protein directly. Instead, they are targeting WWP1, which, because it is an enzyme, offers a good target for drug development.

With the help of Brandeis University biochemist Greg Petsko, the researchers have embarked on a search for a small molecule that can interfere with WWP1 and cause osteoblasts to make more bone.

"There are not many therapies for osteoporosis and the bone loss associated with metastatic cancer," Glimcher said. "What we have done is identify a new player, a novel protein critical in regulating bone formation."