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Transgenic mice help researchers understand the skeletal system
Researchers show the cartilage phase of bone healing is delayed in transgenic mice lacking the tumor necrosis factor alpha family of genes.
Mice have been used in research labs since the early 20th century, but more recently, genetically mutated mice have become crucial to scientists investigating the specific effect of a gene — or lack of a gene — on a function of the body.
Genetically mutated, or transgenic, mice are particularly useful in studying human diseases and defects because the majority of human genes have a counterpart in the mouse genome. By knocking out or overstimulating a gene in mice, researchers can learn more about how that gene might work in humans.
Courtesy of Thomas Einhorn |
Thomas A. Einhorn, MD, chairman of orthopedic surgery at Boston University Medical Center, has studied a family of genes called tumor necrosis factor alpha (TNF-alpha) using transgenic mice. His research has found this family of genes extremely important to the normal function of the skeletal system. By knocking out the genes that code for TNF-alpha-receptors he and fellow researcher Louis C. Gerstenfeld, PhD, were able to study the importance of TNF-alpha family members in the process of fracture healing.
“[TNF-alpha] is a very important gene and we find that the cartilage phase of fracture healing is seriously delayed in animals that can’t express [TNF-alpha],” Einhorn told Orthopedics Today. “Because many of the fractures that don’t heal in people typically result in nonunions in which there is cartilage where there should be bone, we think that the delay in progression from cartilage to bone in these non-union fractures may be related to a failure in the biology of their [TNF-alpha] family of genes ... because our studies in which we knock out [TNF-alpha] produces a situation in mice similar to what we see in patients who have a failed fracture healing situation.”
An important research component
Transgenic mice are increasingly important to musculoskeletal research as orthopedists try to understand how to manage diseases and repair and regenerate tissues. Transgenic mice are created by isolating a fertilized egg from the female and injecting it with something that will either demolish or over stimulate the expression of one particular gene. The mouse then develops without that gene working at all or with it working too hard.
With a five-year grant from the National Institutes of Health, Einhorn and his colleagues are developing an animal model that will allow them to limit over expression or inhibition of a gene to certain tissues and only when they want to. As opposed to the transgenic mouse described above, in this mouse model, researchers would be able to turn off a gene to see how the body reacts without it, then turn it back on to see if the body reacts differently when it is functioning properly. Researchers would also be able to affect genes in specific tissues, rather than all genes as is the case with the transgenic mouse previously used, replicating a more natural situation.
“We’re developing a system that allows us to implant something into the genes of an animal that would be dormant until we trigger it and we would trigger it both in specific tissues and at specific times and that would allow us to understand, for example, what [TNF-alpha] did in early fracture healing versus late fracture healing,” he said.
Making progress
Two years into the project, researchers are on schedule and making good progress, Einhorn said. Once the model is complete, researchers will use it to study how bone morphogenetic proteins affect fracture healing and bone regeneration. “So what we want to do,” Einhorn said, “is either overexpress bone morphogenetic proteins or overexpress something that inhibits bone morphogenetic proteins at specific times and in specific places to understand its role in skeletal healing and skeletal regeneration.”
Einhorn and his fellow researchers hope that other orthopedists will be able to use this mouse model as well to study genes that they’re interested in.