Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Clinical Dentistry

Program

Orthodontics

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Beier, Frank

2nd Supervisor

Tassi, Ali

Co-Supervisor

Abstract

Background: The GSK-3 genes (Gsk3a and Gsk3b) have been known to affect many cellular processes and signaling pathways some of which are implicated in the growth and development of the craniofacial skeleton.

Aim: The purpose of this study was to assess the effect of chondrocyte-specific deletion of Gsk3a and Gsk3b on the size of the mandible and craniofacial skeleton in embryonic mice.

Materials & Methods: Mice were bred to generate cartilage-specific Gsk3a and Gsk3b KO mice. On embryonic day 18.5 (E18.5) the offspring were gathered by caesarian section. Whole mount skeletal staining was completed on the specimens using Alcian blue and Alizarin red. The antero-posterior (AP) dimension of the entire craniofacial skeleton and the mandible was measured, along with the transverse dimension of the cranial vault and the intramandibular angle for each embryo. The investigator was blind to the genotype of embryos in each trial group. Immunohistochemistry was used to detect and localize three proteins, Sox9, Beta-catenin, and Osteocalcin, in the bone and cartilage of E16 mouse skulls.

Results: The specific removal of both Gsk3a and Gsk3b in prenatal cartilage of mice leads to a significant reduction in the antero-posterior length of the total craniofacial skeleton and mandible when compared to wildtype mice. Cartilage-specific Gsk3a/Gsk3b KO mouse embryo display no significant change in the transverse width of the cranial vault. A significant increase in the intramandibular angle is seen in the KO mice when compared to the wild type mice.

Conclusions: Loss of both GSK-3 isoforms in prenatal mice results in significant changes to the size and shape of the facial skeleton and cranium.

Summary for Lay Audience

Orthodontics is a field which utilizes bone growth to move teeth, expand the upper jaw, and to align the upper and lower jaws in a manner which is harmonious to the rest of the skull. Currently mechanical approaches employing brackets, wires, auxiliaries, appliances, and surgical methods are the primary means to manipulate bone growth and achieve orthodontic goals. With advances in molecular medicine research, biological approaches including molecular therapy may provide new avenues to manipulate bone growth. Molecular interventions such as those that target GSK-3, an enzyme involved in skeletal development, may assist orthodontists to treat patients in which unstable dental camouflage or orthognathic surgery are the only viable options. Previous studies have looked at the way the GSK-3 genes affects bone growth, which is commonly done by removing the gene. This study was designed to see if removing both GSK-3 genes from a specific structural component (cartilage) in mice before they are born would change the shape and size of their head or lower jaw. Multiple prenatal mouse skulls were measured using images taken on a microscope of skulls stained to make bone more conspicuous. The measurements of the mice missing the GSK-3 genes were compared to normal mice gathered from the same litter. This study found the mice which had the GSK-3genes removed had a smaller head size in length but not in the width dimension. The mutant mice also had a smaller bottom jaw in the length dimension but bigger in the angular width dimension. This study showed that the GSK-3 gene can alter the growth and development of the craniofacial skeleton in prenatal mice.

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