By investigating the genetic underpinnings behind tooth formation in early human development, a team of scientists in Japan has uncovered clues about how they might be regenerated in adults suffering from congenital conditions. The discovery hinges on a new understanding of the way a specific gene regulates the behavior of molecules known to be key players in tooth development, which the researchers were able to target for promising outcomes in mice and ferrets.
The research, which was conducted by scientists at Japan's Kyoto University and the University of Fukui, begins with the pair of molecules called bone morphogenetic protein (BMP) and Wnt.
These molecules are known to regulate the growth of various organs and tissues during the very early stages of human development, but the team wanted to investigate the way they impact tooth development specifically, and how these processes might be leveraged for regenerative treatments. This led them to a gene called uterine sensitization associated gene-1 (USAG-1).
"We knew that suppressing USAG-1 benefits tooth growth," says lead author Katsu Takahashi. "What we did not know was whether it would be enough."
Because USAG-1 is known to interact with both BMP and Wnt, the scientists suspected that it could provide a pathway to interfere in their behavior. But the trouble with targeting the activity of BMP and Wnt in this way is that it generally affects the whole body, given the wide-ranging functions of the molecules.
This proved to be the case in the team's early experiments, where the team tested the effects of several monoclonal antibodies on USAG-1 in mice with a congenital condition characterized by tooth loss, called tooth agenesis. Indeed, this led to poor birth rates and survival rates, forcing the researchers to search for more selective approach. This led them to one antibody that disrupted the interactions between USAG-1 and BMP only.
Through those experiments, the scientists discovered that the BMP signaling played an essential role in determining the number of teeth the mice ended up with. In one case, delivering a one-off dose of the antibody actually resulted in the generation of an entire tooth that wouldn't have otherwise materialized. Follow-up experiments in ferrets produced similar results.
"Ferrets are diphyodont animals with similar dental patterns to humans," says Takahashi. "Our next plan is to test the antibodies on other animals such as pigs and dogs."
The scientists describe this as the first study to demonstrate how monoclonal antibody drugs can benefit tooth regeneration. Should subsequent experiments on pigs and dogs produce equally promising results, the team imagines the treatment one day becoming an effect approach to tackling congenital tooth agenesis.
The research was published in the journal Science Advances.
Source: Kyoto University via EurekAlert
