August 1, 2001

Mouse Model Sheds Light on Hereditary Dental Defects

Scientists at the NIDCR have created an animal model that mimics two human hereditary dental defects-dentinogenesis imperfecta type II and dentin dysplasia. Their studies of the mouse model offer clues to how these disorders arise.

Dr. Ashok Kulkarni and his colleagues genetically engineered mice that make extra amounts of TGF-b1 (transforming growth factor beta-1) in their teeth. The animals were born with no apparent defects, but at two weeks their teeth became discolored and eventually fractured, leaving behind small stumps. Detailed study of the animals revealed reduced activity of the dspp gene, which produces a protein that is critical for dentin formation. The scientists reported their findings in the April 6 issue of the Journal of Biological Chemistry.

"Our mouse model sheds light on the role of TGF-b1 in tooth development and points to a reduced functioning of the dspp gene as a possible cause of dentinogenesis imperfecta type II and dentin dysplasia," said study author Kulkarni from the NIDCR Functional Genomics Unit and Gene Targeting Facility. "Additionally, this animal model gives us a new tool for developing and testing treatments."

Dentinogenesis imperfecta type II, which affects approximately 1 in 6,000 newborns, is characterized by blue-gray or amber brown opaque teeth. The teeth have narrow roots, are fragile and fracture easily. In dentin dysplasia, tooth color can be normal, or slightly bluish or brownish and opaque. The teeth are shorter and more pointed than normal teeth, and may become loose and fall out because of inadequate root formation. The tooth's dentin is abnormal in both hereditary defects. Dentin, which is a hard material similar to bone, 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.

TGF-b1 Overproduction

Tests revealed that dspp activity was significantly reduced in the mouse model compared to normal animals. "This is the first time that overproduction of TGF-b1 in teeth has been shown to result in reduced functioning of the dspp gene," Dr. Kulkarni said. "We think the gene might contain elements that respond to TGF-b1. Or perhaps other genes, influenced by TGF-b1, may indirectly control dspp." TGF-b1 is a member of the superfamily of TGF proteins that have many diverse functions in normal development throughout the body. It has long been known that TGF-b1 plays a part in tooth development and that it is active in the dentin-forming cells from as early as day 13 in the mouse embryo.

An electron microscope view of the affected animals' teeth showed irregularities in dentin formation, with dentinal tubules short and sparsely distributed. It is through these tiny tubes that dentin-forming cells secrete the proteins that make up dentin's scaffolding. The researchers also found elevated levels and abnormal distribution of collagen I and collagen III, components of the protein scaffolding, in the affected animals' teeth.

Also defective was the mineralization process, in which dentin hardens when calcium is deposited onto its protein framework. In the affected teeth, calcium was unevenly distributed in the dentin, whereas in normal teeth, calcium is distributed uniformly.

The research team will continue to study the regulation of the dspp gene implicated in the development of dentinogenesis imperfecta type II and dentin dysplasia, as well as other genetic and molecular aspects of the disorders.

Collaborating with Dr. Kulkarni's group, which includes Dr. Tamizchelvi Thyagarajan, Dr. Taduru Sreenath and Dr. Andrew Cho, was Dr. J. Tim Wright from the Department of Pediatric Dentistry, School of Dentistry, University of North Carolina, Chapel Hill. ###