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DEDICATIONTo my parents, who have supported my education. iv ACKNOWLEDGMENTSOne of the most important things I have learned during my PhD is the necessity of the existence of a working network of people that can help you achieve your goals. The more effectively this network functions, the higher the chance you will achieve the goals quickly.I would first like to thank my parents, who have unconditionally supported my decision to abandon a profitable private practice in Orthodontics, and return to humble student conditions while aiming for a full time academic career.I also thank my girlfriend Laura Kruter who has (almost always) been ok with my, some might say, not very sane ideas. Sometimes they do turn out fine, though (like this "PhD" one).I can hardly think of anyone else that could have complemented my work and ideas during this Program as well as Dr. Thomas Katona. While I was passionately conditioned to an idea, he was always rational and careful. While I was sometimes furious with a shortcoming, he was always temperate and humorous. When I ran into his office with some news about a project, he would always listen and almost never seem too busy to see me. While I was working and something went wrong, he would listen and wonder with me about the "whys" and "hows", instead of telling me what to do or express disappointment. He was even subject to some of my home culinary experiments. I was extremely fortunate to find someone that thought about science the same way I did, and that actually helped me with my project instead of just telling me what to do. I felt like we worked as a team, and that helped to increase my motivation during my studies. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions viii were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology.The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared.There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.
DEDICATIONTo my parents, who have supported my education. iv ACKNOWLEDGMENTSOne of the most important things I have learned during my PhD is the necessity of the existence of a working network of people that can help you achieve your goals. The more effectively this network functions, the higher the chance you will achieve the goals quickly.I would first like to thank my parents, who have unconditionally supported my decision to abandon a profitable private practice in Orthodontics, and return to humble student conditions while aiming for a full time academic career.I also thank my girlfriend Laura Kruter who has (almost always) been ok with my, some might say, not very sane ideas. Sometimes they do turn out fine, though (like this "PhD" one).I can hardly think of anyone else that could have complemented my work and ideas during this Program as well as Dr. Thomas Katona. While I was passionately conditioned to an idea, he was always rational and careful. While I was sometimes furious with a shortcoming, he was always temperate and humorous. When I ran into his office with some news about a project, he would always listen and almost never seem too busy to see me. While I was working and something went wrong, he would listen and wonder with me about the "whys" and "hows", instead of telling me what to do or express disappointment. He was even subject to some of my home culinary experiments. I was extremely fortunate to find someone that thought about science the same way I did, and that actually helped me with my project instead of just telling me what to do. I felt like we worked as a team, and that helped to increase my motivation during my studies. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions viii were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology.The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared.There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.
Osteoblasts release adenosine triphosphate (ATP) out of the cell following mechanical stress. Although it is well established that extracellular ATP affects bone metabolism via P2 receptors [such as purinergic receptor P2X7 (P2X7R) and purinergic receptor P2Y2 (P2Y2R)], the mechanism of ATP release from osteoblasts remains unknown. Recently, a vesicular nucleotide transporter [VNUT, solute carrier family 17 member 9 (SLC17A9)] that preserves ATP in vesicles has been identified. The purpose of this study was to elucidate the role of VNUT in osteoblast bone metabolism. mRNA and protein expression of VNUT were confirmed in mouse bone and in osteoblasts by quantitative real‐time PCR (qPCR) and immunohistochemistry. Next, when compressive force was applied to MC3T3‐E1 cells by centrifugation, the expression of Slc17a9 , P2x7r , and P2y2r was increased concomitant with an increase in extracellular ATP levels. Furthermore, compressive force decreased the osteoblast differentiation capacity of MC3T3‐E1 cells. shRNA knockdown of Slc17a9 in MC3T3‐E1 cells reduced levels of extracellular ATP and also led to increased osteoblast differentiation after the application of compressive force as assessed by qPCR analysis of osteoblast markers such as Runx2, Osterix, and alkaline phosphatase (ALP) as well as ALP activity. Consistent with these observations, knockdown of P2x7r or P2y2r by siRNA partially rescued the downregulation of osteoblast differentiation markers, caused by mechanical loading. In conclusion, our results demonstrate that VNUT is expressed in osteoblasts and that VNUT inhibits osteoblast differentiation in response to compressive force by mechanisms related to ATP release and P2X7R and/or P2Y2R activity.
Facial esthetics, balance, and harmony, and/or their absence, have attracted attention from time immemorial, by artist and art viewer alike. Facial expressions can readily reflect various moods, emotions, and feelings, thereby conveying unspoken messages from person to person. The mouth is an essential component of this anatomicalphysiological-emotional complex, by virtue of its ability to participate actively in these functions, involving its soft (cheeks, lips, and tongue) and hard (jaws and teeth) tissues. Painters, sculptors, and photographers have noted these features, and frequently, when creating images of human faces, included the rest of the body, or at least the torso, in their artwork, demonstrating acceptance of the principle that the face and the rest of the body are one unit. The specialty of orthodontics is taught predominantly as a field of endeavor dedicated to the improvement of orofacial esthetics and function. Consideration of biological principles and constraints is shadowed by the desire of both the patient and his/her orthodontist to achieve noticeable improvement in the position and location of the malpositioned crown(s), ignoring the fact that the crowns are anchored in the jaws by their roots, which are surrounded by tissues that act and react like any other organ to any local or systemic factor that comes their way. This situation is like an iceberg, visible partially above the water surface, but invisible under it.Malocclusions are situations where individual teeth or entire dental arches are positioned in undesirable locations, either esthetically or functionally. The goal of orthodontics is to correct or minimize deviations from accepted normal
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