Genetic, Mechanical and Pharmaceutical Modulation of Bone Formation in Zebrafish

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Osteoporotic bone fragility is a major clinical issue, leading to increased fracture incidence. This can be underpinned either by genetic causes, changes due to hormonal shifts, or can be induced by long-term use of glucocorticoids, known as glucocorticoid- induced osteoporosis (GIOP). There is still an unmet need for effective osteoanabolic therapies, particularly ones that are non invasive. Zebrafish are increasingly used as a model for skeletal biology, due to their rapid development, translucency of larvae and some bone tissues throughout life and their genetic tractability. This thesis investigates the relationship of genetics, pharmaceuticals and vibration in bone development and homeostasis. My data reveal that early glucocorticoid exposure significantly inhibits skeletal, immune, and vascular development in zebrafish, with lasting effects on bone growth and regeneration at later stages. This study also explores the potential of vitamin K supplementation and nano-vibration as osteoanabolic therapies, I showed that both can lead to increased osteoblast number, changes to chondrocyte maturation and to vascular lumenisation. In my final chapter, I studied zebrafish mutants of two genes known to impact bone health in mammals: sost and lmx1ba. My study surprisingly revealed that zebrafish sost mutants do not have any obvious skeletal phenotypes, suggesting differences in gene function or compensatory mechanisms between zebrafish and mammals. By contrast, lmx1ba mutant zebrafish showed developmental changes to skeletal patterning, particularly in the spine, with progressive phenotypes that lead to severe skeletal spinal phenotypes in adults. These results underpin the utility of the zebrafish as a model for skeletal studies and give results that could inform future studies that move towards translation.
Date of Award7 May 2024
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorDanielle M Paul (Supervisor) & Chrissy L Hammond (Supervisor)

Keywords

  • zebrafish
  • bone
  • glucocorticoids

Cite this

'