Gerald Crabtree, investigator at Howard Hughes Medical Institute (HHMI) and 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.

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 - tend 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.

Cyclosporine inhibits a signalling 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. Winslow, Crabtree, and their colleagues found that mice with the hyperactive NFATc in their osteoblasts had an immense increase in bone mass compared to normal mice.

When the researchers examined the cells in these mice, they found that up-regulating NFATc signalling 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.

“Mice with abnormally active NFATc probably develop so much bone mass because this delicate balance between osteoblasts and osteoclasts has been altered,” Crabtree suggested. This imbalance between bone formation and degradation could potentially be recreated by drug treatments for osteoporosis, Crabtree said. Very little NFATc1 must be activated to build extra bone, Winslow noted, which means that it may be possible to up-regulate the calcineurin/NFATc pathway to promote bone formation without disturbing other organ systems that use this same pathway.; Source: Howard Hughes Medical Institute (HHMI)