Altering Osteoclasts In Utero Leads to Changes in Mandibular Lengths in Adult Mice
- Author(s): Vargas, Ricardo Luis
- Advisor(s): Jheon, Andrew
- et al.
Craniofacial skeletal malocclusions often involve the hyper- or hypo-morphogenesis of the maxilla and/or mandible. Although genetic and environmental factors are thought to play important roles in the etiology of skeletal malocclusions, specific contributions of either factor are yet unclear. To determine whether alterations in osteoclastic activity during embryonic/fetal development changes lead to changes in mammals jaw lengths, we utilized three mouse models to alter osteoclast activity during development.
First, we injected in vivo siRNA specific to cathepsin K (Ctsk), a gene expressed highly in osteoclasts to decrease Ctsk and in turn, osteoclast activity in pregnant dams at embryonic day 12.5. Second, we generated genetically modified CtskCre;DTAfl/+ (diphtheria toxin A) mice, which led to an increase in osteoclasts. Third, we fed Time-mated FVB wildtype mice high calcium and low phosphorous diets during gestation. Changes in offspring osteoclast activity were confirmed by tartrate-resistant acid phosphatase (TRAP) assay. Micro-computed tomography and three-dimensional (3D) geometric morphometrics revealed changes to 6-week old mouse craniofacial morphology. Downregulation of Ctsk by siRNA led to decreased osteoclast activity and was associated with an increase in mandibular body length. Conversely, an increase in osteoclast activity in CtskCre;DTAfl/+mice was associated with a decrease in mandibular body length. Increased calcium and decreased phosphorus levels in utero led to a retrognathic mandible associated with lowered BMD in experimental females, whereas experimental males showed partly opposite effects Our study demonstrates that alterations in osteoclast activity during gestation leads to 3D shape changes in the adult mandible.