© 2014, LISA CLARK. ADAPTED FROM FIGURE 7, ROT ET AL.
EDITOR'S CHOICE IN PHYSIOLOGY
C. Rot et al., “A mechanical jack-like mechanism drives spontaneous fracture healing in neonatal mice,” Dev Cell, 31:159-70, 2014.
When people break a bone, they usually go to an orthopedist to straighten out any misaligned pieces so that the bone does not heal crookedly. But doctors have long observed that when infants get fractures—even if they receive minimal medical intervention—their bones heal reasonably straight.
The assumption had been that fractures in infants at first heal crookedly and then are reshaped through bone remodeling, a lifelong process by which old or damaged bone is resorbed and replaced. But researchers at the Weizmann Institute of Science in Rehovot, Israel, showed that mouse bone fragments realign themselves before fusing back together.
To better understand the healing process, the researchers broke bones in the front legs of newborn mice. They then allowed the mice to move about freely and took periodic computed tomography (CT) scans as the fractures healed. Within 28 days, fractures with broken-bone angles less than 40 degrees had completely realigned themselves, while more severely misaligned fractures didn’t heal perfectly straight but significantly improved.
The researchers also labeled the bones’ surfaces with fluorescent markers, finding the colorful coatings remained intact during realignment, indicating realignment was happening by physical movements of the bones, rather than by remodeling of their surfaces.
When a fracture occurs, a fibrocartilaginous material called soft callus, made up of osteoblasts, chondrocytes, and fibroblast-like cells, forms around the break. Staining tissue from the area of the fracture, the researchers noticed that the soft callus was asymmetrical, with an excess of chondrocytes on the concave side of the angled break. Moreover, when they analyzed chondrocyte gene expression in the callus, they saw an enrichment of markers characteristic of bidirectional bone growth plates—like those that help a developing skull expand—on the concave side of the fracture. Unlike most growth plates, which form new bone only in one direction, the plate in the fracture’s bend appeared to be moving in two opposite directions. The researchers hypothesize that the forces thus generated push the bone fragments into alignment.
Realignment was “a very fast process,” says coauthor Elazar Zelzer. “It basically happened before the fractured bones were united and ossified.” Only once the bones were aligned did the soft callus connecting them fully harden.
When the researchers paralyzed mice’s muscles by injecting them with Botox, the bones healed crookedly, and the growth plates did not appear. Zelzer says he does not know why having functional muscles is important for realignment, but he speculates that muscle contractions help cells sense the extent of the fracture and direct growth plate formation.
“It’s no doubt that they’ve identified a bidirectional growth plate,” says Jill Helms, a professor at the Stanford University School of Medicine. However, Helms remains skeptical about whether such a growth plate can actually generate enough force to counteract muscle contractions that pull the fractured bone into its angulated position. “That’s a question that I guess remains for the next series of experiments,” she says.
“If we are able to understand more about our new process,” says Zelzer, “we may be able to come up with new ideas about how to improve fracture healing in pathological situations.”