The transcriptome of regenerating zebrafish scales identifies genes involved in human bone disease

Zebrafish scales are mineralised plates that can regenerate involving de novo bone formation. This presents an opportunity to uncover genes and pathways relevant to human musculoskeletal disease relevant to impaired bone formation. To investigate this hypothesis, we defined transcriptomic profiles of ontogenetic and regenerating scales, and identified 604 differentially expressed genes (DEGs) that were enriched for extracellular matrix, ossification, and cell adhesion pathways. Next, we showed that human orthologues of DEGs were 2.8 times more likely to cause human monogenic skeletal diseases (P<8×10 −11 ), and they showed enrichment for human orthologues associated with polygenetic disease traits including stature, bone density and osteoarthritis (P<0.005). Finally, zebrafish mutants of two human orthologues that were robustly associated with height and osteoarthritis ( COL11A2 ) or bone density only ( SPP1 ) developed skeletal abnormalities consistent with our genetic association studies. Col11a2 Y228X/Y228X mutants showed endoskeletal features consistent with abnormal growth and osteoarthritis, whereas spp1 P160X/P160X mutants had elevated bone density (P<0.05). In summary, we show that transcriptomic studies of regenerating zebrafish scales have potential to identify new genes and pathways relevant to human skeletal disease.