Abstract
AbstractOsteogenesis imperfecta (OI) is a heterogeneous group of rare genetic diseases characterized by increased bone fragility and deformities. The pathomechanisms of OI are poorly understood, hindering the development of disease-specific therapy. Addressing the limited understanding of OI and the lack of targeted treatments remains a challenge, given its varied symptoms and large clinical spectrum. Animal models have greatly advanced the understanding of the disease; however, the heterogeneity and subtype-specific symptoms are difficult to translate to humans.In vitromodels offer a promising tool for translational medicine, as they have the potential to yield patient-specific insights in a controlled environment using patient derived-cells. We used mechanically loaded 3D-bioprinted patient-specific organotypic bone models and time-lapsed micro-computed tomography to demonstrate dysregulation of mineralization inFKBP10-related OI compared to healthy controls. In contrast to healthy controls, tissue mineral density and stiffness were decoupled, such that hypermineralization observed in OI samples did not lead to increased stiffness. Additionally, we were able to replicate experimental stiffness using sample specific micro-finite element analysis. This allowed us to show mineral formation in regions of high local strain, suggesting mechanoregulation inFKBP10-related OI organotypic bone models is comparable to healthy controls. Regional analysis of mineralization showed increased heterogeneous mineralization, microarchitectural inhomogeneities and scaffold microporosity of OI samples compared to healthy controls. Our results suggest that the observed dysregulation of mineralization is the main driver for the altered mineral-mechanics properties observed inFKBP10-related organotypic bone models.One Sentence SummaryOrganotypic bone models demonstrate dysregulated mineralization in osteogenesis imperfecta samples compared to healthy controls.
Publisher
Cold Spring Harbor Laboratory