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Title: The principles of dermal and endochondral ossification
Author: Gibbs, Sophia
ISNI:       0000 0004 6423 130X
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2017
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The mammalian skull is a complex ossified structure of multiple embryological tissue origins. It is formed from two distinct forms of ossification: intramembranous ossification that produces the flat dermal bones of the calvaria craniofacial region and the mandible, and endochondral ossification that forms the cranial base. I investigated the patterns of mineralisation in both bone types, in the dermally ossifying frontal bone and the endochondrally ossifying cranial base. I also investigated the cell behaviour within the frontal bone and expansion of chondrocytes clones in the cranial base synchondroses. I find that the intramembranously ossified frontal bone displays complex and novel forms of biomineralisation, including a system of intercalary biomineral thickness growth that cannot be explained by the current accepted model of dermal ossification. I discover that the cells associated with the specialised biomineralised architecture of the dermal bone, contribute to its growth via a novel mechanism of bi-directional cellular invasion from the outer layers of the bone to the intervening mineralising layer. Cell behaviour is found to depend upon the direction of invasion for preosteoblasts, which also show a distinct invasive pattern compared to other cell types. I discover a number of previously unknown cell types that possess invasive behaviour, including a double positive RUNX2+HAND+ population and neural crest derived endothelial cells in the dermal bone, which co-express the endothelial growth factor VEGFA. Ablation of VEGFA and of HAND2 in the neural crest lineage prevents invasion of the frontal bone and a loss of thickness growth of biomineral respectively. My analysis of the cranial base reveals a cryptic modularity of growth of its separate bones and cartilages that varies with time. I also find the synchondroses of the cranial base not to be the origin of biomineral growth as expected but discover a system of radial and longitudinal intercalary biomineral growth similar to that observed in the frontal bone. My findings suggest that the timing of growth and ossification of bone is crucial for proper development, and this may inform the pathophysiology of cranial base syndromes than have complex timing of the onset symptoms. It suggests hints that the ancient mechanisms of biomineral growth in dermal bone are co-opted for use by tissues that ossify in an endochondral fashion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology