A New Way to Build Bone

Howard Hughes Medical Institute (HHMI) researchers at Stanford University have found that they can increase bone mass in mice by tweaking the shape of a regulatory protein.

HHMI investigator Gerald Crabtree and HHMI predoctoral fellow Monte Winslow report that slightly increasing the activity of a protein called NFATc1 causes massive bone accumulation, suggesting that NFATc1 or other proteins that regulate its activity will make good targets for drugs to treat osteoporosis. They report their findings in a study published in the June 6, 2006, issue of Developmental Cell.

In vertebrates, bone is constantly being formed and being broken down throughout life. Cells called osteoclasts continuously degrade bone, while cells called osteoblasts replenish it.

"Ideally, they are perfectly balanced," said Crabtree, the senior author of the study. "Over the course of a lifetime, if everything goes well, we'll maintain almost exactly identical bone mass." However, if the balance is upset, and more bone is destroyed than formed, osteoporosis results, increasing the risk of fractures.

The new study arose from the researchers' curiosity about reports that patients who were treated with the drug cyclosporine - often given to suppress the immune system before organ transplants - tended to lose bone mass. Those patients were also at increased risk of bone fractures, said first author Winslow, who led the study as an HHMI predoctoral fellow in Crabtree's lab. Winslow is now working as a postdoctoral fellow in the lab of HHMI investigator Tyler Jacks at the Massachusetts Institute of Technology.

Cyclosporine inhibits a signaling protein complex known as calcineurin, which chemically modifies the NFATc family of proteins. This modification changes its shape. With its new shape, NFATc can move into the nucleus of the cell, where it can trigger the activation of many genes. Although initially shown to regulate immune cell function, NFATc also functions in other cells to regulate heart development, blood vessel formation, neural development and function, and muscle development. Its function seems to depend on the time and place of its activation, like a context-sensitive key on a computer. In bone, it is NFATc1 that seems particularly important.

Since people with suppressed calcineurin/NFATc activity experience bone loss, Winslow, Crabtree, and their colleagues wanted to see whether this pathway would be important in bone development and function as well. They studied mutant mice in which the NFATc1 in osteoblasts had been modified so that it could move more easily to the nucleus and become a little more active than usual.

Mice with the hyperactive NFATc in their osteoblasts had an immense increase in bone mass compared to normal mice, suggesting that the balance between bone formation and breakdown had tipped.

When the researchers examined the cells in these mice, they found that up-regulating NFATc signaling in osteoblasts increased the numbers of both types of bone cells. "It was clear that increased NFATc activity in osteoblasts influenced both osteoblasts and osteoclasts," Winslow said.