Adult zebrafish can replace bones when they lose a tail fin. Knowing how they do it might lead to better ways to treat bone fractures in people, researchers say.
Zebrafish have amazing innate abilities to regenerate lost appendages and organs, says co-author Kryn Stankunas, professor of biology at the University of Oregon and a member of the Institute of Molecular Biology.
Stankunas and colleagues have identified two molecular pathways that work in concert for zebrafish. One pathway resets existing bone cells to a developmental stem cell-like state and then supports their growth to replace lost cells. The second directs the newly formed cells to turn back into functional, organized bone.
In a study published in the journal Cell Reports, they explain how the opposing pathways cross-communicate to keep the regenerative process in balance.
Perfectly restored lost tissue
Stankunas says a mysterious process triggers residual cells to revert to a less developed state upon tissue damage, a process known as dedifferentation. The process is unique to animals like zebrafish and could be the key to their ability to perfectly restore lost tissue.
“We focused on the bones of the zebrafish tail fin,” Stankunas says, “and asked how amputation induces mature bone-lining cells to go backwards in their developmental age to what’s called a progenitor state.”
The researchers found that cell-to-cell signaling mediated by the Wnt pathway helps existing mature bone cells become progenitor cells after fin amputation. This starts the bone regeneration process.
Local Wnt production at the tip of the regrowing fin then maintains a pool of dividing bone progenitor cells until the fin is fully replaced. The job of second pathway, BMP, is to convert the progenitor cells back into mature bone that forms the characteristic bony rays of a fish’s fins.
The authors show that both Wnt and BMP are needed to complete the process and describe how they engage in a cellular tug of war to balance their opposing roles.
New therapies for humans
Mammals, including humans, have these same pathways, and defects in them are associated with various human bone diseases, says the paper’s lead author Scott Stewart, an associate member of the Institute of Molecular Biology.
Manipulating the two pathways could lead to new therapies, he says. “Striking that balance involves manipulating these pathways in the correct sequence, Wnt and then BMP. They have different roles and must act in a specific order.”
The US Food and Drug Administration has approved the use of recombinant BMP to encourage bone-growth following some surgical procedures.
However, Stankunas says, the treatment is not always effective. The new findings suggest that too much BMP may upset the optimum balance of Wnt and BMP signaling, and that alternative approaches may be more successful.
“Our research suggests that enhancing human bone repair or even inducing bone regeneration isn’t a ridiculous idea,” he says.
“As we discover the cellular and molecular roles of the signals in zebrafish and pinpoint the missing network connections in mammals, maybe we could coax human bones to repair themselves equally as well.”
The National Institutes of Health funded the work.
Source: University of Oregon