The role of osteoclasts in the development of Class III skeletal malocclusions

Craniofacial skeletal disharmonies present some of the most difficult challenges to orthodontists. Correcting class II (e.g., mandibular retrognathism) and class III (e.g., mandibular prognathism) skeletal discrepancies frequently requires extractions or orthognathic surgery. It is yet unclear how skeletal malocclusions arise but there is evidence for a genetic basis. However, the role of environment and local factors in determination of mandibular length is unknown, but the balance between bone formation and resorption likely influences mandibular length. Experiments performed in avian models where the presence and/or activity of osteoclasts during craniofacial development was inhibited showed effects on beak lengths. For example, inhibition of osteoclasts or bone resorbing cells using the bisphosphonate alendronate during early development (e.g., before mineralization of craniofacial bones) led to an increase in lower beak length (e.g., sagittal length). Conversely, activation of osteoclasts led to a decrease in lower beak length. From these results, we hypothesize that alteration of osteoclasts during development leads to effects on mandibular length in mammals. To test this hypothesis, we employed 2 distinct methods in mice: 1) we inhibited osteoclasts with alendronate in utero at E12.5; and 2) we eliminated osteoclasts by generating CtskCre;DTAfl/+ mice. The second method would reduce osteoclasts by the expression of diphtheria toxin (DTA) wherever Ctsk or cathepsin K, an osteoclast marker, is expressed. Specimens were scanned using micro-computed tomography and cephalometric analyses performed. Alendronate treatment in utero resulted in slightly increased sagittal length of the mandible. CtskCre;DTAfl/+ mice had slightly smaller mandibles and cranial base bones relative to their overall size due to a surprising increase in osteoclasts compared to controls. These data will lay the foundation for future experiments to further understand the role of osteoclasts in determination of mammalian mandibular lengths