Gage Crump and his colleagues at the University of Southern California have used the regeneration of zebrafish jawbone to demonstrate that the regeneration of damaged bones does not necessarily require a recapitulation of the same processes that occur during embryonic development. Even though this work used zebrafish as a model system, it may provide some of the underlying principles for treating difficult fractures.
Cartilage production is critical for healing full-thickness bone injuries. In order to understand how this bone-producing cartilage is generated, Crump and his coworkers turned to the genetically malleable and relatively more simple zebrafish system. Zebrafish are vertebrates, like humans, but these animals retain a remarkable capacity to regenerate many of their organs.
When human bones fracture, a small cartilage callus forms that is replaced by bone that bridges small, but not large, gaps in the bone.
In zebrafish, however, the cartilage callus continues to expand and fills even very large gaps in broken bones. This cartilage is replaced throughout the bone by bone. This allows zebrafish to heal even very large fractures.
These days, patients with severe bone fractures may have a surgeon insert metal pins and even plates to help set bone. In more severe cases, bone grafts are used to span gaps, and stem cell-based treatments have been tested in a few clinical trials as well.
About six million people in the U.S. suffer bone breaks each year, and even though most of these patients recover fully, about 300,000 are slow to heal and some may not heal at all. Complications include post-traumatic arthritis, growth abnormalities, delayed union and misaligned union.
Hundreds of professional football players have invested in stem cell treatments to treat injuries, even though the evidence for the efficacy of such treatments is, sometimes, sparse. One report even tells of an NFL linebacker who paid $6,000 for a 1-milliliter vial of donated placenta tissue containing stem cells to be injected into his injured knee.
The bone surface contains thin lining called the “periosteum” that contains a stem cell population that helps maintain bone mass throughout one’s life. In Gage’s laboratory, his team identified a gene called Indian Hedgehog a (IHHa), which is responsible for inducing these periosteal stem cells to switch from bone production to cartilage production. Mutant zebrafish strains that lack the IHHa gene are unable to make cartilage in response to bone injury and heal poorly from bone fractures.
Crump said that an “exciting finding from our work is that, somewhat counterintuitively, cartilage is critical for healing full thickness bone injuries. By understanding how this bone-producing cartilage is generated in the simpler zebrafish model, we hope to find ways to create more of this unique cartilage tissue in patients to better heal their bones.”
According to this paper, which was published in the journal Development, 2016; dev.131292 DOI: 10.1242/dev.121292; instead of the more traditional approach of using bone cells or bone-like materials to heal broken bones, stimulating endogenous bone-based stem cells that make this special kind of fracture-healing cartilage might be a more effective strategy.