Establishing an organotypic bone fracture model for Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a genetically and phenotypically heterogeneous collection of rare genetic disorders. It is characterized by increased bone fragility, which results in frequent fractures, especially during childhood. Most cases are caused by mutations in either COL1A1 or COL1A2, the genes encoding the alpha-chains of type I collagen, the main organic part of bone. However, in recent years, new mutations in more than twenty collagen-related genes have been found to cause OI. Despite the different causes, hypermineralization is a common feature of the great majority of OI cases. Current treatments, such as bisphosphonates, often fail in preventing bone fractures. This fact could be attributable to shortcomings of OI models. Indeed, animal models fall short in recapitulating the genetic and molecular characteristics of the human condition. In vitro organotypic bone models represent a promising tool for targeted and personalized medicine, as they can be developed employing patient-derived cells. In this study, we used mechanically loaded 3Dbioprinted patient-specific organoids and weekly micro-computed tomography to investigate the effects of teriparatide, a drug which is gaining attentions in OI management. Moreover, we also used the same tools to assess the altered mineralization in COL1A2-related OI compared to metabolically healthy controls. The results demonstrated an improvement in the dynamic stiffness of OI treated organoids, but there was no difference for the mineralization parameters. Moreover, the results showed only limited evidence of the hypermineralization feature in OI samples when compared to metabolically healthy controls. Overall, patient-derived organotypic bone models proved being a promising tool for disease modelling and testing therapeutic interventions.