Figure 5

Zebrafish models of endochondral growth zone development and disease (A) Model for the patterning of growth zones (GZs) based on genetic studies of mouse long bones (82–84). Indian hedgehog (Ihh) is first expressed in the nascent diaphysis of the cartilage model. Its expression domain expands towards the epiphyses and activates Parathyroid hormone-like hormone (Pthlh) expression in periarticular cartilage. Pthlh represses Ihh at a distance, which sets the distance between the hypertrophic zone (HZ) and resting zone (RZ). (B) Model for the patterning of CH GZs in zebrafish based on (46). pthlha is expressed at the epiphyses of the differentiating CH. The HZ is then patterned by pthlha and muscle contractions before the onset of ihha expression. According to this model, ihha plays a role in the maintenance of GZs, not their patterning. (C) Zebrafish fam20b mutants recapitulates the skeletal phenotype of Raine syndrome, a particular form of osteosclerotic bone dysplasia (45). Short overossified long bones are observed in Raine syndrome newborns. Premature ossification of the CH diaphysis is observed in zebrafish fam20b mutants. (D) Zebrafish chimaeras recapitulate the formation of cartilage nodules observed in the human condition hereditary multiple exostosis, which results from a mutation in the EXT2 gene. ext2-/- chondrocytes are excluded from WT cartilage stacks in zebrafish chimaeras, leading to the hypothesis that osteochondromas observed in EXT2+/- patients result from loss-of-heterozygosity (85). Ihh and ihha expression domains in yellow, Pthlh and pthlha expression domains in pink, ectonucleoside triphosphate diphosphohydrolase 5a (entpd5a) expression domain in light blue, cartilage in blue, and bone in red. CH, ceratohyal; GPs, growth plates; WT, wild type; dpf, days post-fertilization.