Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models

The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish (Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.