Revealing Physiology of Craniofacial Growth Zones Through Pathology
Creators: Roth, Daniela M.
Publisher: name: University of Alberta Library
Year: 2024

<p>This thesis addresses critical gaps in our foundational understanding of craniofacial biology, particularly in elucidating the cellular responses in mechanically loaded craniofacial growth zones. By bridging disparate yet interconnected fields, it aims to provide a comprehensive insight into cell behavior within craniofacial structures. Specifically, this study delves into the dynamics of sutures separating different craniofacial bones, highlighting two understudied sutures: the internasal and mid-palatal sutures. <br>
In the introductory literature reviews comprising Chapters 1 and 2, I explored the significance of mechanistic biological reasoning and its integration into clinical interpretation and treatment. I synthesized evidence of shared biological principles across research disciplines, specifically focusing on their application to cranial sutures. Chapter 1 introduces cranial sutures and explores the biological mechanisms underlying their pathophysiological widening, emphasizing the diversity of modalities leading to a shared clinical outcome. Chapter 2 delves into the current body of knowledge on mechanotransduction, its integration with major signaling pathways, and their synergistic control over cell differentiation within sutures. The methodology used in the primary research chapters is summarized in Chapter 3.<br>
The experimental studies in results Chapters 4 and 5 investigated cellular and molecular responses to the deletion of specific Bone Morphogenetic Protein (Bmp) family members, focusing on Bmp2 and Bmp7 and their implications for suture biology. Chapter 4 presents a high-resolution study of the internasal suture deviation in Bmp7 neural crest knockout mice, revealing Bmp7&#39;s role in localized osteoblast differentiation signaling and facial symmetry. My follow-up study, detailed in Chapter 5, describes the effects of deleting Bmp7 or Bmp2 from Gli1+ osteoprogenitor cells. The most prominent malformation was observed at the cranial base synchondroses, another type of craniofacial growth zone.  Comparison with global or neural crest-specific Bmp2 and Bmp7 deletions showed distinct morphological and molecular changes affecting embryonic and postnatal cranial base development. These findings underscore the diverse functional roles of Bmp family members beyond ossification, with implications for oromaxillofacial reconstruction and potential off-target effects. Importantly, suture obliteration due to premature ossification was not observed in any of the genetic models utilized in this thesis. This allowed for an examination of osteogenic regulation within a distorted yet intact developmental system using a multiomic approach. Finally, in Chapter 6, I investigated suture establishment in the palate in a wild type model. The study of the mid-palatal suture provided insights into suture patency, forces in morphogenesis, and the establishment of osteogenic structures. This enabled a reciprocal comparison to cranial sutures, revealing significant overlap in pathways, including known craniosynostosis risk genes and hypothesized patency factors.<br>
In the final chapter,  this thesis provides a comprehensive discussion of paradigms in suture biology, examining snapshots across the suture’s natural lifespan. A key message is that the broad usage of the term &#39;patency’ hinders collective interpretation of the dynamic nature of craniofacial growth zones, including suture morphogenesis, functional growth, and the concept of quiescence. The results in this thesis underscore the importance of further translational studies linking clinical pathology to context-based osteoprogenitor behavior at a foundational level.</p>