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- Mechanisms of de novo bone formation in a fish model of fin regenarationPublication . Silva, João Pedro Gonçalves Cardeira da; Laizé, Vicent Stéphane; Gavaia, Paulo JorgeUnveiling the basis of animal tissue regeneration may contribute to the better understanding of disease mechanisms and the development of novel therapeutic strategies. Regeneration-competent animals are also valuable tools in drug discovery and for studying basic mechanisms of development. Bone is a dynamic tissue, formed and maintained through a balance between matrix deposition by osteoblasts and resorption by osteoclasts. When bone remodelling fails to homeostatic equilibrium, degenerative and dysplastic diseases may develop. Moreover, human bone is unable to completely restore structure and function after trauma. Hence, this work aimed at uncovering novel players in bone formation and patterning in an innovative system, the zebrafish regenerating caudal fin. A comprehensive set of imaging and analytical methodologies were first development and optimized to track bone formation and regeneration in a precise and timely manner throughout fin epimorphic regeneration. To gain insights into cellular and molecular programs underlying bone regeneration, the transcriptome of regenerates at distinct stages (blastema formation and regenerative outgrowth) was analysed. RNA-Seq data pointed toward a role of osteoclasts and calcitonin in ray patterning. Calcitonin-specific inhibition of osteoclast activity impaired ray bifurcation and demonstrated the central role that osteoclasts play in this process. Evidence toward calcitonin-specific regulation of osteoclast differentiation in the context of ray bifurcation, was also collected. To further study the mechanisms underlying bone formation, a swim-training regeneration model was established. In this model, bone formation during regeneration was stimulated and ray bifurcation was accelerated upon increased mechanical loading, further demonstrating the suitability of this system to investigate underlying mechanisms. This work provided valuable technical advancements for the study of bone regeneration in zebrafish and identified novel players in ray formation and patterning (i.e. bifurcation). Altogether, this work also proposes the zebrafish bifurcating fin ray as a potential model for tetrapod digit specification and associated diseases.