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.
