The zebrafish as a model for fragile bone disorders

Fragile bone disorders (FBD) are characterized by increased fracture risks due to insufficient or fragile bone. Osteogenesis imperfecta (OI) is a hereditary bone disorder that is mostly caused by dominant mutations. Recently, also genes for autosomal recessive forms of OI have been identified, which are mainly involved in collagen biosynthesis, secretion and processing, osteoblast differentiation and bone mineralization. Only a few monogenetic forms of osteoporosis are known, which are linked to mutations in genes such as WNT1 and PLS3. In this study, we aimed at investigating the relevance of the zebrafish for FBD disease modeling by studying the phenotypic and molecular characteristics of zebrafish models for different types of FBDs. This was done for OI-related genes such as type I collagen genes and plod2/fkbp10 but also for genes involved in familial osteoporosis such as wnt1 and pls3. Initial characterization of the skeleton was performed by whole mount Alizarin red staining, revealing abnormalities in the vertebral column in most OI models, but not in osteoporosis models. Additionally, high-resolution Micro CT of adults was performed for a more detailed analysis. This showed, significant differences in Tissue Mineral Density (TMD) and bone volume. These experiments illustrate the high phenotypic similarity of these zebrafish mutants with human FBDs. Interestingly, there is a relatively large phenotypical variability present within each genotype, a finding which is also observed in human patients even when carrying the same mutation. In conclusion, we present zebrafish models for different types of OI and monogenic osteoporosis and show the potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in FBDs.

Jaar van publicatie:2019