Investigating the role of autophagy in musculoskeletal development and homeostasis using zebrafish

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Autophagy is a key catabolic process responsible for the removal of waste and damaged cell components by lysosomal degradation. It plays an important role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for the development and survival of bone and cartilage cells, and for skeletogenesis. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders, including the joint disease, osteoarthritis (OA). OA is the most common cause of arthritis globally and one the biggest causes of disability, affecting 15% of the UK population. It is characterised by the progressive degeneration of articular cartilage at the joint interface, leading to exposure of the underlying bone and joint misalignment, pain, and loss of function.

In this thesis, the role of autophagy-related genes: atg13 and lmx1b, in skeletal development and joint function was explored using zebrafish lines mutant for these genes. Loss of autophagy activity in the atg13 mutants caused an acceleration to chondrocyte (cartilage cell) maturation, leading to changes in extra-cellular matrix (ECM) formation and restricted jaw joint mobility. These results are consistent with autophagy contributing to the regulation of chondrocyte maturation which supports joint formation and function. Meanwhile, characterisation of the lmx1b mutant lines demonstrated that the lmx1b paralogues, lmx1ba and lmx1bb have divergent roles in zebrafish development, affecting skeletal and neuronal development, and renal development, respectively. Whilst loss of both paralogues (lmx1b dKO) resulted in muscular abnormalities and reduced body growth. As adults, loss of lmx1b caused skeletal changes reminiscent of premature OA and behavioural changes, suggesting a role for lmx1b in skeletal and neuronal development and maintenance. Overall, these results expand our understanding of the roles played by autophagy and lmx1b in cartilage and joint development, among other systems, broadening our understanding of OA pathogenesis.
Date of Award21 Jun 2022
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJon D Lane (Supervisor) & Chrissy L Hammond (Supervisor)


  • Autophagy
  • Zebrafish
  • LMX1B
  • Atg13
  • skeletal development

Cite this