Researchers at the University of California, Berkeley, have found that calcium, the main constituent of bone, plays a major role in regulating the cells that orchestrate bone growth.

The finding, which came from study of the signals that tell undifferentiated stem cells in the very early embryo to mature into bone cells, could affect treatment for conditions caused by too much collagen deposition, such as fibrosis and excessive scarring, and diseases of too little bone growth, such as Treacher Collins Syndrome (TCS), and could also explain how messing with the body's calcium levels during pregnancy can cause facial deformities such as those associated with fetal alcohol syndrome.

"You would basically add calcium to cells on those support structures, which is fairly easy, and motivate chondrocytes to secrete the collagen that is needed to build a bone structure on top of that support," said Michael Rape, the Dr. K. Peter Hirth Chair in Cancer Biology in the Department of Molecular and Cell Biology at UC Berkeley and an investigator at the Howard Hughes Medical Institute. "That would be exciting, but it is very much in the future. Nevertheless, this might become a possibility the more we understand about how cells make their decisions."

Last year, Rape's lab identified an enzyme, called CUL3, that adds a protein known as ubiquitin to the protein TCOF1 and makes stem cells mature into neural crest cells, from which the jaws, inner ear and numerous other bones in the head and face develop. When both copies of TCOF1 are mutated, the embryo dies. But if only one of the two copies of TCOF1 is mutated, as in the craniofacial disorder TCS, fewer neural crest cells are produced and many die early, leading to improper bone growth in the skull.

In his new study, published online on Thursday in the journal Cell, Rape searched for the signals that turn on ubiquitylation enzymes like CUL3, allowing the developing embryo to form bone at the right time and in the right place in the organism. He found that CUL3, which not only triggers stem cells to become neural crest cells, but stimulates chondrocytes to secrete collagen, needs the help of two calcium-binding proteins.

"Our research basically identifies calcium not only as a structural element of bone, which makes the bone strong and sturdy, but also as a signaling molecule for bone formation that we hadn't appreciated before, which can be used to turn enzymes on and off," he said. "Calcium is a very important regulatory molecule that allows the organism to make cell-fate decisions."

"This means is that you basically have many different steps that come together in order to form a bone, and that they are beautifully orchestrated by calcium," Rape said, acknowledging that further research is needed before physicians can attempt regenerative therapies to help those born with TCS. "The more you understand about each of these steps, the easier it is to focus your applied research onto things that matter and change something for these patients."