Engineering bone phenotypes in domestic animals: Unique resources for enhancing musculoskeletal research

Abstract The utility of genetic engineering has increased significantly in recent years, particularly with the wide acceptance of CRISPR-Cas9 genome editing technology. The wide application of genome editing techniques provides a unique opportunity for musculoskeletal investigators to consider the examination of rare (and other) disease phenotypes as well as gene function in domestic animals. It is particularly important to consider developing domestic animal models of bone disorders in which the bone remodeling process parallels that observed in humans and since rodent models have not fully recapitulated the phenotype of the homologous human mutations. In contrast to the use of larger animal models, rodent experiments are less costly and time-consuming, making genetically engineered small animal models (primarily rodents) widely attractive for studying bone metabolism. However, many important issues not fully addressed in small animal models remain, such as Haversian remodeling, metaphyseal fracture healing and the development and evaluation of orthopedic implants. Once generated, a specific bone phenotype in a domestic large animal model has the potential to uncover new mechanistic insights into bone remodeling, specific details of muscle-bone-tendon and ligament interactions, and provide an opportunity for improved treatment and/or targeted therapeutic interventions that are mechanism-based. In this perspective, we interrogate the modeling of bone phenotypes in domestic animals and evaluate the role of these species in the growth of the musculoskeletal field, considering the high current preference for rodent models. Whatever the eventual outcome, it is clear that recent biotechnology developments in gene editing and the growing list of well-annotated genomes is bringing significant changes to the way bone phenotypes are developed, studied and evaluated.