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 functi
Contact: Jennifer Donovan
Howard Hughes Medical Institute