Increased NFATc1 activity substantially increases bone mass

NATFc controls the expression of genes in the Wnt signaling pathway that regulate osteoblast proliferation.

Recently, investigators discovered that slight increases in the activity of the protein NFATc1 results in the “massive” accumulation of bone mass. Now a study by researchers at the Howard Hughes Medical Institute at Stanford University, Calif., suggest NFATc1 or other proteins that regulate its activity may be effective targets for osteoporosis drugs.

The researchers began studying NFATc1 following recent reports that cyclosporine causes reductions in bone mass, according to Gerald R. Crabtree, MD, a Howard Hughes Medical Institute (HHMI) investigator and professor of pathology and of developmental biology at Stanford University School of Medicine.

Cyclosporine is frequently used to suppress the immune system in organ transplant patients. The drug inhibits calcineurin, which chemically modifies the NFATc protein family, changing its shape, according to Crabtree.

“[NATFc] controls the expression of genes in the Wnt signaling pathway that regulate proliferation of osteoblasts,” Crabtree told Orthopedics Today. “It also controls the expression of genes that induce the migration of osteoclast progenitors into bone, thereby allowing them to develop into osteoclasts.”

HHMI investigators knew that mice who had hyperactive NFATc in their osteoblasts experienced a significant increase in bone mass. This suggested that NFATc has a significant affect on the balance between bone breakdown and formation, according to a news release.

In an experimental study, published in the journal Developmental Cell, Crabtree and colleagues mutated mice to allow NFATc1 to move more easily to osteoblasts’ nuclei and increase in activity. This caused an imbalance in the number of osteoblasts to osteoclasts, with osteoblasts outnumbering osteoclasts. The increased NFATc also caused osteoblasts to increase expression of chemokines, the inflammatory proteins that promote osteoclast development.

Crabtree noted that only a small increase in NFATc is needed to increase bone mass accumulation. “In fact, it seems that if you increase the nuclear NFATc by only 10%, there is a substantial increase in bone mass,” he said.

However, much more research remains before the new discovery could affect osteoporosis treatment clinically. Researchers are now looking for ways to increase NFATc without causing side effects.

“I think it is too early to be certain that this will be an effective approach to treating osteoporosis, but it does represent a possibility,” Crabtree said.

Scott Boden, MD, director of the Emory Spine Center and professor of orthopedic surgery at Emory University School of Medicine, Atlanta, and editor of Orthopedics Today’s spine section, noted that such discoveries as this are gradually becoming more common. However, the challenge is in taking such observations about sensitive regulatory proteins and developing a pharmacologic product that has a viable delivery strategy and acceptable risk profile, he told Orthopedics Today.

“In the meantime, such observations give us increasing hope that there will be more sophisticated strategies for bone formation in the future, which may offer better treatments for osteoporosis and other systemic metabolic bone disorders,” Boden said.

For more information:
Winslow MM, Pan M, Starbuck M, et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell. 2006;10:771-782.