Engineering 3D biomimetic osteogenesis imperfecta models to dissect mechanisms of N-cadherin mediated osteoblast-endothelial function

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Project Summary/Abstract Osteogenesis Imperfecta (OI) is a rare disease characterized by low and inappropriate bone formation resulting in bone fragility. OI is caused by loss-of-function or dominant-negative mutations in a major ECM component, named type 1 collagen (composed of COL1A1/COL1A2 genes). There is currently no cure for OI, and long-term benefits of current treatments remain unclear in terms of fracture reduction and bone functionality. OI affects bone homeostasis which is governed by the function of various cell types and their spatial arrangement in three-dimensions (3D) through association with collagen scaffolds. Specifically, signaling interactions among endothelial cells, nerve cells, osteoblasts, osteoclasts, osteocytes and their shared collagen matrix may control their function and dramatically impact bone homeostasis. (Aim 1) To decouple each cell contribution to OI, we will develop a robust preclinical screening model, based on the organ-on-a-chip technology, that recapitulates the bone microvasculature with the surrounding cells, such as osteoblasts. This platform will be used for drug screening and identification of new OI therapeutics, avoiding the limitations of laborious and expensive in vivo and in vitro studies. (Aim 2) To further expand our studies, we will use these 3D disease-like organ-on-a-chip systems to dissect the heterocellular mechanisms of COL1A1 aiming at identifying new gene targets for OI and ultimately, developing new strategies for prevention. Specifically, we aim to understand the role of an adheren junctions (AJs) molecule, named N-cadherin in bone microvasculature by dissecting the mechanisms mediating osteoblast-endothelial coupling. Given the recognized fundamental importance of multicellular complexity in numerous bone diseases, these in vitro models would decouple important mechanisms involved in multiparametric bone-related diseases such as osteoporosis or bone cancer. Overall, these new in vitro microphysiological systems can be regarded as controlled, physical representations of specific patients and therefore be applied directly in the clinic to inform strategies for treatment or prevention of disease.