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Researchers Identify Gene that Regulates Joints

by Patricia McBroom, Public Affairs
posted August 19, 1998

A gene that is crucial in regulating the formation of skeletons and joints has been identified by researchers at Berkeley and Harvard.

This genetic switch, called "noggin," tells embryonic cells to stop making bone and begin creating a joint. Mouse embryos that were genetically engineered without the noggin gene failed to develop joints. Instead, their bones grew into stubby, continuous limbs.

These unusual results were reported in the May 29 issue of Science magazine by Richard Harland, Berkeley professor of molecular and cell biology, and research associate Lisa Brunet, with Harvard University scientists Jill and Andrew McMahon. Their research was funded by the National Institutes of Health.

"We were completely surprised by the finding," said Harland, who noted that clinical research on noggin could lead to its use in combating conditions of excessive bone deposits. In 10 percent of hip replacements, for example, bone growth is over stimulated. In other, more rare conditions, connective tissue turns to bone, creating immobile joints.

"We think noggin is a signal that allows developing cells to stop making bone and begin creating a joint," said Harland. "In the absence of it, you get too much bone formation."

It is not yet known whether noggin is active in the metabolism of adult bones. If so, this genetic switch also could be relevant in treating diseases caused by insufficient bone formation, such as osteoporosis.

First discovered in 1993 by Harland, noggin was originally thought to be a gene that induced nerve cell development. Its name was taken from experiments with frogs that had overly large heads and an unusual amount of undeveloped neural tissue. In fact, the gene does not directly induce nerve cell growth, but it switches the very early embryonic cell toward the path that makes nerve cells instead of skin cells.

Later experiments showed that noggin's basic action is to inhibit the powerful proteins that induce bone formation. Noggin actually binds with and prevents the action of bone morphogenic proteins (BMPs), said Harland.

In fact, noggin and BMPs are basic switches that operate throughout the developmental sequence for the growth of bone, skin and nervous tissue, said Harland.

"BMPs and noggin appear to be alternate switches for positive and negative activity," said Harland. "Depending on the location of the developing tissue, the BMPs tell embryonic cells to make bone or skin, while noggin tells the cells to stop doing that."

The latest experiment, conducted by Brunet, revealed that noggin is particularly important in the process that forms cartilage which then develops into new bone. The researchers had not expected such striking effects on bones because they did not think the mice would live long enough to have fully developed limbs.

"We thought these mice would die early because they wouldn't have a brain or spinal cord," said Harland. "That was not the case."

In fact, the mice were born with a nervous system -- although a seriously under-developed one. What was particularly striking, however, was the lack of knees and knuckles. The legs and feet formed without any joints.

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