Japanese Scientists Discover Potential to Regrow a Third Set of Teeth

Envision a world where teeth can be replaced, not with dentures and implants but with an antibody-based treatment approach. Scientists in Japan unearthed a medicine focusing on regeneration that could help humans grow a third set of teeth.

What's the story behind this regenerative approach?

A story of tooth formation in human life includes two successive sets of teeth, namely primary and permanent teeth, the so-called diphyodont. In addition to that, a third dentition focuses on one or more teeth that are partially apart from the permanent dentition, in humans, deciduous or milk teeth are the foremost teeth, except for molars, permanent teeth belong to the second generation. 

What's the third set of teeth?

The third set of teeth is the extra set of teeth in addition to primary and permanent teeth.

Studies in the 19th century revealed the existence of a third dentition in a few mammals. In humans, a rudimentary epithelium was identified after a century. Ooë et al. marked that the epithelium that helps in forming the third dentition grows lingual to the permanent tooth germs.

Detection of the third dentition during early childhood encourages the visualization and portrayal of hyperdontia in the mouth of infants and some fetuses.

So the identification of the third dentition is crucial and helps in exploring its potential for successful tooth regeneration.

Regeneration of the teeth with the help of activating the third dentition is considered a scientifically viable approach.

Have a look at the journey of the scientific Progress of the Takahashi group and the investigators

A common health condition in almost all age groups is tooth loss. But considering tooth loss might be due to different reasons:

1. Congenital 

2. Acquired

Focusing on congenital conditions, any absence of one or more teeth as a result of failure in the tooth development process during the early stage of tooth formation is known as tooth agenesis. There are different classifications, and one of the classifications includes syndromic and non-syndromic agenesis.

Advances in molecular, imaging technologies, and next-generation sequencing, also different underlying causes, have been reported about the role of genetics and genomic variants in non-syndromic tooth agenesis and their influence on tooth agenesis and associated medical conditions.

Tooth agenesis has been a topic of prior important studies in different animal models. 

Looking into genetics and the studies 

The understanding of tooth genetics is crucial, as identification and examination of the genetic factors that help to regulate the interactions between the epithelial and mesenchymal cells. The number of teeth in every species is usually determined, and the researchers made breakthroughs by demonstrating how rudimentary incisor teeth persist and grow as supernumerary teeth due to the inactivation of USAG-1( Uterine sensitization associated gene-1).

A timeline sequence of Takahashi studies

1998 and 2001- Adenocyte mediated gain of function Msx 2 expression.

2007- USAG-1 abrogation and supernumerary tooth formation.

2008- USAG-1 deficient mouse and supernumerary teeth formation.

2014- USAG-1 and BMP-7 interactions and supernumerary teeth formation

2016-  USAG-1 and BMP-7 deficiency and impact on murine tooth morphogenesis.

2017- Wnt10a in Japanese congenital tooth agenesis.

2018 and 2019- Third dentition is the main cause

2021- Therapeutic potential of USAG-1 and USAG-1 siRNA in tooth regeneration.

With identification and reporting of mice with USAG-1 deficiency and supernumerary teeth in 2007, Takahashi et al, 2023, employed mouse models and molecular techniques to reveal successful tooth regeneration. Studies included on administration of single systemic and dose-dependent USAG-1-targeting antibodies in EDA1-deficient (Ectodysplasin-1) and wild-type mice ameliorated tooth agenesis have resulted in the promotion of natural tooth formation. The antibodies, which are generated by neutralizing USAG-1, have action on BMP signaling and also reduce low Lrp5/6 dosage recovered the USAG-1-null phenotype, including hyperdontia. Several mice have died in this Lrp5/6 study, thereby providing information on Wnt signaling regulation. 

Takahashi et al. further aimed to focus on the shortcomings and improved their observational studies, focusing on the protein analysis of USAG-1 targeting antibodies, which revealed an association between USAG-1 and Msx-1 and a successful regeneration of a tooth in mice with tooth agenesis noted.

A single systemic administration of USAG-1 targeting antibodies did not cause any side effects in the lineage of mice.  These findings brought a correlation of USAG-1 targeted antibodies and EDA-1 deficient mice that could help in promoting tooth regeneration, furthermore highlighting the important role of USAG-1 in tooth agenesis.

Takahashi et al analyzed 78 patients where the third dentition is the cause of additional teeth. Researchers also revealed that on systemic application of USAG-1 targeting antibodies in ferrets could regenerate a tooth identical to the third dentition. This result is uplifting as ferrets share a similar dental pattern to those of humans. The clinical application of USAG-1 targeting antibodies that regenerate lost teeth needs additional safety and efficacy assurance in nonrodent models.

Any precise factors to control for all 28 teeth is not determined. The administration of an anti-USAG-1 antibody help to control the eruption of a regenerated tooth with accurate morphology, correct eruption timing, adequate calcification, and region. Because USAG-1 protein has only the possibility to save the developmental arrested tooth germ, which had been programmed to a certain tooth type.

Although this was a mouse study, the possibility of similar results in humans is still promising. Showcasing these results in humans would support the suggestion of “third dentition,”.

The tooth regeneration is very effective by usage of the Anti-USAG-1 antibody treatment in mice, and this can be a breakthrough in treating tooth anomalies in humans.

References

1. Ravi, V, A Murashima-Suginami, H Kiso, Y Tokita, CL Huang, K Bessho, J Takagi, M Sugai, Y Tabata, and K Takahashi. "Advances in Tooth Agenesis and Tooth Regeneration." Regenerative Therapy 22, (2023): 160. Accessed March 17, 2025. https://doi.org/10.1016/j.reth.2023.01.004.

By Dr. Lakshmisahithi Tanneru

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