Clinical pathologies of bone fracture modelled in zebrafish

• Published in: Disease models & mechanisms 2019-09, Vol.12 (9)
• Main Authors: Tomecka, Monika J, Ethiraj, Lalith P, Sánchez, Luis M, Roehl, Henry H, Carney, Tom J
• Format: Article
• Language: English
• Subjects: Alendronate - pharmacology; Alendronate - therapeutic use; Animal Fins - pathology; Animals; Bacterial infections; Bisphosphonate; Bisphosphonates; Bone; Bone density; Bony Callus - drug effects; Bony Callus - pathology; Callus; Diphosphonates - pharmacology; Diphosphonates - therapeutic use; Disease Models, Animal; Fracture; Fracture Healing - drug effects; Fractures; Fractures, Bone - drug therapy; Fractures, Bone - microbiology; Fractures, Bone - pathology; Fractures, Ununited - pathology; Infections; Mutation; Neutrophils; Osteoclasts - drug effects; Osteoclasts - pathology; Osteogenesis imperfecta; Osteogenesis Imperfecta - pathology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - physiology; Transplants & implants; Zebra; Zebrafish; Zebrafish - physiology
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.037630

Reduced bone quality or mineral density predict susceptibility to fracture and also attenuate subsequent repair. Bone regrowth is also compromised by bacterial infection, which exacerbates fracture site inflammation. Because of the cellular complexity of fracture repair, as well as genetic and environmental influences, there is a need for models that permit visualisation of the fracture repair process under clinically relevant conditions. To characterise the process of fracture repair in zebrafish, we employed a crush fracture of fin rays, coupled with histological and transgenic labelling of cellular responses; the results demonstrate a strong similarity to the phased response in humans. We applied our analysis to a zebrafish model of osteogenesis imperfecta (OI), which shows reduced bone quality, spontaneous fractures and propensity for non-unions. We found deficiencies in the formation of a bone callus during fracture repair in our OI model and showed that clinically employed antiresorptive bisphosphonates can reduce spontaneous fractures in OI fish and also measurably reduce fracture callus remodelling in wild-type fish. The mutant, which has reduced osteoclast numbers, also showed reduced callus remodelling. Exposure to excessive bisphosphonate, however, disrupted callus repair. Intriguingly, neutrophils initially colonised the fracture site, but were later completely excluded. However, when fractures were infected with , neutrophils were retained and compromised repair. This work elevates the zebrafish bone fracture model and indicates its utility in assessing conditions of relevance to an orthopaedic setting with medium throughput.This article has an associated First Person interview with the first author of the paper.