It may sound counterintuitive, but the most common type of human dwarfism results when cells in a child’s bones are overstimulated by growth factors. A mouse study, however, suggests that injecting such children with a molecular decoy that sponges up these factors could treat the condition.
People with the form of dwarfism called achondroplasia rarely stand more than 1.5 meters tall. The mutation responsible for the condition ends up stunting the growth of the long bones in the arms and legs, bowing the vertebral column, and often constricting the passage through which the spinal cord runs. Along with short stature, the condition can cause difficulty walking; fluid buildup around the brain; and apnea, or the temporary inability to breathe. Although researchers haven’t identified a treatment for achondroplasia, they have uncovered the molecular flaw that triggers it. As a typical child’s bones elongate, cartilage cells called chondrocytes mature and then die, allowing hard, bony material to supplant them. In children with achondroplasia, a genetic flaw causes a receptor on the surface of these chondrocytes to be hyperactive. When stimulated by molecules called fibroblast growth factors, this receptor, known as FGFR3, prevents the cells from maturing and impedes bone formation.
To calm this overzealous receptor, molecular biologist Elvire Gouze of INSERM in Nice, France, and colleagues resorted to deception. They repeatedly injected a solution of FGFR3 into mice that had a growth-hindering condition equivalent to achondroplasia. The researchers hypothesized that these free-floating copies of the receptor would serve as decoys, capturing fibroblast growth factor molecules and reducing stimulation of the cartilage cells’ receptors. That’s what appeared to happen. The treatment restored normal growth in the mice and forestalled skeletal defects characteristic of achondroplasia, the researchers report online today in Science Translational Medicine. Injections of the decoy cut the percentage of mice that showed abnormal curvature of the spine from 80% to as little as 6%, depending on the dose. When the treated mice matured, the females gave birth to normal numbers of pups, another sign that the skeleton—specifically, the pelvis—had reached full adult size.
FGFR3 injections benefitted the mice in another way, cutting their mortality rates by more than two-thirds. “We suppressed complications,” Gouze says. “They don’t have problems breathing, they don’t have paraplegia [inability to walk] anymore.” After dissecting the animals, weighing their organs, testing their blood, and scrutinizing their tissues under the microscope, she and her colleagues didn’t detect any signs of ill effects from the treatment. The team plans further studies on mice to confirm the approach’s safety and to nail down the optimal schedule for doses, she says.
“I think it’s a really exciting paper,” says clinical geneticist William Horton of the Shriners Hospital for Children in Portland, Oregon. “It clearly shows that if you give this agent, the bones grow.” Medical geneticist Jacqueline Hecht of the University of Texas Medical School at Houston concurs. Growth in a bone occurs in a region called the growth plate, and Hecht says the study suggests that the injected FGFR3 “restores the growth plate and increases bone growth. You really can’t ask for more.”
Decoy FGFR3 is among four molecules that have recently shown promise for sparking bone growth; a tweaked version of one molecule, C-natriuretic peptide (CNP), has already gone through human safety trials. But Hecht notes that although CNP breaks down within minutes in the body, decoy FGFR3 lasts for hours and produces normal growth in the mice with just twice-weekly injections. The new treatment “is the best by far” of these approaches, she says. What researchers should do now, Horton says, is test all four molecules in mice to determine which one causes the fewest side effects and provides the best results. “At some point there needs to be a direct comparison,” he says.