No bones about it: gene vital to skeleton.

When is a mouse like a shark?

When you eliminate the gene Cbfa1.

True, it's not the funniest riddle around, but bone researchers may enjoy it. Mice missing the Cbfa1 gene don't form bones, which leaves them with a skeleton made only of cartilage, like sharks. Unlike sharks, however, mice need a bony skeleton, so the unfortunate rodents die at birth.

Four reports in the May 30 Cell and one scheduled for the July 1 Journal of Cellular Biochemistry describe the discovery that Cbfa1 is vital to bone-forming cells, or osteoblasts.

"I think its the most wonderful series of papers I've seen in a long time," says Jane E. Aubin, an osteoblast researcher at the University of Toronto.

The new findings offer "a very compelling, exciting, and solid story on bone development," adds Bjorn R. Olsen of Harvard Medical School in Boston.

Olsen and his group came across Cbfa1 during a search for the genetic mutations that cause cleidocranial dysplasia syndrome (CCD), a rare human skeletal disorder. As infants grow, bone formation closes several soft spots in the skull. In people with CCD, those spots remain open. Many also lack a clavicle or major portions of it, a defect that allows some of them to bring their shoulders together below their chin.

"We were interested in this disorder because we thought it might tell us something about bone formation," says Olsen.

As his team hunted for the CCD gene, Olsen heard that two other groups had created mice with a similar skeletal disorder by mutating the mouse Cbfa1 gene. The human version of this gene lies in the chromosome 6 region where Olsen's group was looking. The investigators report in Cell that people with CCD have mutations in one of their two copies of Cbfa1.

Two other reports in Cell, one from a research group led by Toshihisa Komori of Osaka University in Japan and the other from a group headed by Michael J. Owen of the Imperial Cancer Research Fund in London, describe mice that have mutations in one or both copies of Cbfa1. When one copy is defective, the mice suffer symptoms similar to CCD. When both copies are, the mice have no osteoblasts.

In normal mammals, osteoblasts form bone by laying down an extracellular matrix and then fortifying it with minerals. In some parts of a skeleton, such as the clavicle and the soft spots of the skull, they do this directly. In others, the body creates an initial cartilage framework.

"This cartilage is degraded, and the space that is created is invaded by bone-forming cells," explains Olsen. Since mice missing both copies of the Cbfa1 gene create no osteoblasts, the animals never replace their cartilage, which is insufficient to support breathing lungs.

The fourth Cell report fleshes out the details of why osteoblasts require Cbfa1. Gerard Karsenty of the University of Texas in Houston and his colleagues had looked for proteins that activate bone-making genes. The protein encoded by Cbfa1 fills the bill, they found.

This DNA-binding protein can turn on many of the genes normally active in osteoblasts. The scientists conclude that it converts osteoblast progenitors into mature bone-forming cells.

The report to be published in July adds support to that hypothesis. Jane B. Lian of the University of Massachusetts Medical Center in Worcester and her colleagues found that when they stop the production of Cbfa1's protein, they prevent osteoblasts grown in test tubes from maturing and creating bonelike structures.

One question raised by the new research is whether doctors may someday use Cbfa1 or its protein to generate new bone in adults, perhaps to treat osteoporosis, a condition in which bone structure decays. Current treatments for the condition focus almost exclusively on stopping degradation rather than trying to spur bone growth, notes Olsen.