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In recent years, Danio rerio (zebrafish) has become widely used as small animal model for human diseases. This is because of the unique characteristics of the embryo such as small size, rapid external development, and transparency of the larval body. These advantages encourage the use of live imaging and powerful genetic tools based on mutagenesis. Besides, automated systems have been coupled with zebrafish embryo to create one of the most important in vivo methods for drug discovery, drug screening, and toxicity testing.
As vertebrates, the zebrafish and mammalian skeletons are very similar. Although mechanics of the mammalian (terrestrial) and fish (aquatic) skeletons differ owing to their habitats, their similarities are strongest at the level of basic cellular functions of osteocytes and chondrocytes and their primary role of secreting extracellular matrix (ECM). The similarity of the adult skeletal structure between Danio rerio and Homo sapiens has hired zebrafish as an animal model to study multiple aspects of skeletal physiology and pathology: bone metabolism, resorbing activity, and tissue turnover. Within the transparent body of zebrafish, morphogenetic processes and physiological activities of the skeleton are easily accessible, and the osteocytes and chondrocytes can be labeled with simple stains, allowing for rapid and high-throughput assessment of the skeleton.
Zebrafish models have been generated for many genes associated with human genetic disorders that affect the skeleton. These human disorders include craniosynostoses, osteogenesis imperfecta (OI), as well as general dysplasias. Genes affecting mineral metabolism include transcription factors, collagen-associated genes and signaling molecules, matrix proteins.
Table 1. Selection of genetic models in zebrafish for human genes associated with bone mineral density (BMD) GWAS
| Human Gene | Human GWAS or Disease/Trait | Zebrafish Phenotype (age) |
|---|---|---|
| COL11A1 | Stickler/Marshall syndrome; Estimated BMD | Abnormally thick and sparse fibrils in the cartilage extracellular matrix/perichordal sheath |
| CYP26 | Coronal craniosynostosis; Estimated BMD | Fusions of the vertebral centra, cartilaginous outgrowths of the endochondral fin elements (dolphin; larvae); Coronal Craniosynostosis (stocksteif; juvenile) |
| ENPP1 | hypermineralization of the axial skeleton; BMD | Patchy mineralization of craniofacial bones; ectopic calcifications; overexpress spp1 (Osteopontin; 6–9 dpf); fusion in vertebral bodies, neural and haemal arches (juvenile) |
| JAG1 | Alagille syndrome; BMD | Facial defects; dorsal hyoid and mandibular arch fusion (5 dpf) |
| LRP5 | Osteoporosis-pseudoglioma (OPPG), craniosynostosis; BMD | Severe defects in the ventral craniofacial skeleton (7 dpf) |
| MEF2C | Auriculocondylar syndrome; BMD | Malformed faces; ventrally displaced jaws. Ectopic cartilage; dorsal/ventral joints missing; enlarged ventral hyoid bone (5 dpf) |
| RUNX2 | Cleidocranial dysplasia; Estimated BMD | Morphants displayed no overt abnormalities (3.5-5dpf) |
| SPP1 | BMD | Reduction in the formation of endochondral and dermal bone (5–15 dpf) |
| SOX9 | Campomelic dysplasia; BMD | Curly-down body axis (4–5 dpf); actinotrichia missing (double mutant) |
| TGFB2 | Estimated BMD | Shortening and misshaping of the jaw, parasphenoid, and ethmoid plate |
Creative Biogene has long-standing experience in conducting preclinical zebrafish model studies of skeletal disease. We can offer multiple routes of gene depletion strategies to generate the zebrafish model, including classical chemical mutagenesis, insertional mutagenesis, gene knockdown by morpholino oligonucleotide (MO) injections, and CRISPR/Cas9 genome editing systems. Many pathological models have been established in adult zebrafish at Creative Biogene, such as bone injury models, osteogenesis imperfecta models, osteoporosis models, arterial calcification models, and osteoarthritis models. These zebrafish models have shown high correspondence of clinical output with human patients affected by skeletal diseases.
Creative Biogene has the expertise and experience to assist you in assessing the therapeutic potential of your compounds for the skeletal disease. Contact us today to discuss your objectives and how we can reach them.
References
For research use only. Not intended for any clinical use.
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