PUBLICATION

Clinical pathologies of bone fracture modelled in zebrafish

Authors
Tomecka, M.J., Ethiraj, L.P., Sánchez, L.M., Roehl, H.H., Carney, T.J.
ID
ZDB-PUB-190807-16
Date
2019
Source
Disease models & mechanisms   12(9): (Journal)
Registered Authors
Carney, Tom, Roehl, Henry
Keywords
Bisphosphonate, Bone, Callus, Fracture, Osteogenesis Imperfecta, Staphylococcus aureus, Zebrafish
MeSH Terms
  • Alendronate/pharmacology
  • Alendronate/therapeutic use
  • Animal Fins/pathology
  • Animals
  • Bony Callus/drug effects
  • Bony Callus/pathology
  • Diphosphonates/pharmacology
  • Diphosphonates/therapeutic use
  • Disease Models, Animal
  • Fracture Healing/drug effects
  • Fractures, Bone/drug therapy
  • Fractures, Bone/microbiology
  • Fractures, Bone/pathology*
  • Fractures, Ununited/pathology
  • Osteoclasts/drug effects
  • Osteoclasts/pathology
  • Osteogenesis Imperfecta/pathology
  • Staphylococcus aureus/drug effects
  • Staphylococcus aureus/physiology
  • Zebrafish/physiology*
PubMed
31383797 Full text @ Dis. Model. Mech.
Abstract
Reduced bone quality or mineral density predict both susceptibility to fracture and also attenuate subsequent repair. Bone regrowth is also compromised by bacterial infection, which exacerbates fracture site inflammation. Due to the cellular complexity of fracture repair, as well as genetic and environmental influences, there is a need for models which permit visualisation the fracture repair process under clinically relevant conditions. We have employed a crush fracture of fin rays, coupled with histological and transgenic labelling of cellular responses to characterise the process of fracture repair in zebrafish and show strong similarity to the phased response in humans. We apply our analysis to a zebrafish model of Osteogenesis Imperfecta (OI), which shows reduced bone quality, spontaneous fractures and propensity for non-unions. We find deficiencies in the formation of a bone callus during fracture repair in our OI model, and that clinically employed anti-resorptive bisphosphonates can reduce spontaneous fractures in OI fish and also measurably reduce fracture callus remodelling in WT fish. The csf1ra mutant, which has reduced osteoclast numbers, also shows reduced callus remodelling. Exposure to excessive bisphosphonate, however, disrupts callus repair. Intriguingly, neutrophils initially colonise the fracture site, but are later completely excluded. However when fractures are infected with Staphylococcus, neutrophils are retained, compromising repair. Together, this work elevates the zebrafish bone fracture model and indicates its utility for assessing conditions of relevance to the orthopaedic setting with medium throughput.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes