Scientists Create Mouse Model That Mimics Human Dental Disorder Study Shows Molecular Events that Contribute to Its Development
A team led by scientists at the National Institute of Dental and Craniofacial
Research (NIDCR) has created a mouse model with tooth defects similar to those
of people with dentinogenesis imperfecta III. The model will allow scientists
to learn more about how the hereditary disorder arises and provides a tool
for developing and testing treatments. The researchers report their findings
in the July 4 issue of the Journal of Biological Chemistry.
Dr. Ashok Kulkarni and his colleagues created the mouse model by
deleting or 'knocking ou' the dentin sialophosphoprotein (DSPP)
gene, thought to be responsible for coordinating the mineralization
of a tooth's dentin. The animals' teeth showed discoloration,
large pulp cavities, and pulp exposure. Detailed studies of
the teeth revealed abnormalities in the dentin. Dentin is
a hard material similar to bone that makes up about three-fourths
of an adult tooth. It lies between the outer enamel and the
innermost core of the tooth called the dental pulp.
"Our study shows that DSPP plays a key role in orchestrating
the process of dentin mineralization, or maturation," said
senior author Dr. Kulkarni from the NIDCR Functional Genomics Unit
and Gene Targeting Facility. "This mouse model shows for the
first time some of the molecular events regulated by DSPP that are
involved in dentin mineralization. For example, we found that
DSPP probably regulates two proteoglycans, or proteins, during this
process, something we didn't expect to find." Dentin formation
requires several steps: First, dentin-forming cells secrete
the proteins that make up dentin's scaffolding. Mineralization
occurs as dentin hardens when calcium is deposited onto this framework.
The areas that are first to mineralize grow and then fuse to create
one calcified mass that is the mature dentin.
Dentinogenesis imperfecta, classified into three subtypes, occurs in about
1 in 8,000 newborns in the U.S. The teeth can be bluish or brownish with
a somewhat translucent appearance. On x-ray, the teeth of patients with
dentinogenesis imperfecta III (DGI-III) appear as 'shell teeth,' with
a layer of enamel, a thin layer of dentin, and very large pulp chambers. Because
of the unstable dentin, the enamel can shear off and expose the dentin, which
could then wear down to the pulp. Most of those severely affected with
DGI-III are candidates for dentures or implants by age 30 despite dental intervention.
In-depth studies of the DGI-III animal teeth revealed an abnormally large
area of unmineralized dentin, or predentin, and an irregular border between
the predentin and its mature counterpart. Additionally, there was evidence
of partially mature dentin trapped between areas that were fully mineralized. In
a normal tooth, the mature dentin would be mineralized completely, the scientists
said.
Other studies found unusually large amounts of two proteoglycans called decorin
and biglycan within the unmineralized areas. "The theory is that
these two proteoglycans help promote mineralization," said Dr. Taduru
Sreenath, the study's first author. "But without DSPP to give
the correct instructions, these proteins are too active and, in fact, interfere
with the process." Dr. Sreenath explained that in normal dentin,
decorin and biglycan are probably degraded and then mineralization proceeds.
Collaborating with Drs. Kulkarni and Sreenath were NIDCR's Tamizchelvi
Thyagarajan, Bradford Hall, and Glenn Longenecker; Rena D'Souza from
the University of Texas Health Science Center at Houston; Sung Hong and J.
Tim Wright from the University of North Carolina, Chapel Hill; Mary MacDougall,
from the University of Texas Health Science Center at San Antonio; and John
Sauk from the University of Maryland at Baltimore.
The NIDCR is one of the National Institutes of Health in Bethesda, Md. NIH
is an agency of the U.S. Department of Health and Human Services.
|