The bodily movement of the dentoalveolar organ involves continuous modeling of the alveolar socket in the direction of the movement while maintaining the thickness of the periodontal ligament and the integrity of the dental root cementum. The movement of teeth and their surrounding bony attachment apparatus is important for the life of organisms: a disrupted tooth row allows for food particles to be retained and cause caries, reduces the chewing and cutting efficacy of the dentition, diminishes individual esthetics, and affects physiological speech and/or vocalization. Under physiological conditions, the intricate microarchitecture of the dentoalveolar organ is little affected by tooth drift, resulting in the bodily displacement of the entire dentoalveolar organ while maintaining the integrity of the alveolar bone sockets, the thickness of the periodontal ligament, and the surface covering of the tooth roots (root cementum). Alternatively, the process of teeth erupting beyond the plane of occlusion within their sockets is called supereruption. The displacement of the entire dentoalveolar complex in mesial (humans) or distal direction (rodents) is termed drift. The dentoalveolar complex is a unique functional and structural entity susceptible to relative displacement in relationship to the underlying jawbone. Together, these data demonstrated that YAP/TAZ signaling is essential for the microarchitectural integrity of the periodontium by regulating mineralization gene expression and preventing excessive resorption during bodily movement of the dentoalveolar complex. The unloaded state of the unopposed molar model in Wnt1Cre/YAP/TAZ mutant mice also caused a significant three-fold increase in osteoclast numbers, a substantial increase in bone/cementum resorption, pronounced periodontal ligament hyalinization, and thickened periodontal fiber bundles.
Application of the unopposed mouse molar model to transform the periodontal ligament into an unloaded state and facilitate the distal drift of teeth resulted in an overall increase in mineralization-associated gene expression, an effect that was 10–20% diminished in Wnt1Cre/YAP/TAZ mutant mice.
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Illustrating the key role of YAP on mineralization gene expression, the YAP inhibition-related downregulation of mineralization-associated genes was reversed by the extracellular matrix YAP activator agrin. The rescue of YAP signaling with the heparan sulfate proteoglycan agrin resulted in a return of the nuclear YAP signal. Cyclic strain applied to periodontal ligament cells resulted in YAP nuclear localization, an effect that was abolished after blocking YAP. Loss of YAP/TAZ was associated with a reduction of mineralized tissue density in cellular cementum and alveolar bone, a downregulation in collagen I, alkaline phosphatase, and RUNX2 gene expression, an increase in the resorption markers TRAP and cathepsin K, and elevated numbers of TRAP-stained osteoclasts.
To ask how the Hippo pathway affects mineralized tissue homeostasis in a tissue that is highly reliant on a tight homeostatic control of mineralized deposition and resorption, we determined the effects of YAP/TAZ dysregulation on the periodontal tissues alveolar bone, root cementum, and periodontal ligament. YAP and TAZ are essential transcriptional co-activators and downstream effectors of the Hippo pathway, regulating cell proliferation, organ growth, and tissue homeostasis.
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