Epigenetic and Environmental Regulators of Early Bone Development
Abstract
Bone formation is a complex, yet key process in the early development of all vertebrates. Therefore, understanding bone development, and more specifically the early stages of bone development, is crucial to further enhance our overall understanding of embryo development as well as finding ways to ameliorate skeletal birth defects. During development bones are derived from mesenchymal cells that either form from mesoderm (axial, paraxial, and lateral) or neural crest origins. These different origins and their derivatives contribute to specific bones in vertebrate organisms.
Origin determination and the subsequent bone formation are tightly controlled processes regulated by signaling pathways, microRNAs (miRNAs), transcription factors and environmental factors. All four elements have been the subject of many studies. However, our understanding of the precise role that miRNAs play in the early stages of bone development, and specifically in early cell fate decisions is lacking. This thesis aims to improve the understanding of miRNAs and their role in origin determination and osteoblast potentiation.
Furthermore, birth defects may arise when normal development is interrupted, delayed or otherwise negatively affects as is the case with exposure to environmental toxicants during embryonic development. The most common exposures, cigarette smoke and various cigarette smoke components, have been shown to reduce bone density and inhibit osteoblast formation. But as with miRNA studies, our understanding of the role that these toxicants play in early development faulters. Therefore, the second aim of this thesis is to elucidate the extent of damage caused by different types of cigarette smoke and tobacco products on early bone development.
Our work shows that miR-690 enhances osteogenesis and alters cell fate through CTNNB1 and FOXO3A inhibition. In addition, we showed that cigarette smoke inhibits early cartilage and bone formation consistent with earlier work from our lab showing cigarette smoke inhibition of FOXO3A and in vitro osteogenesis.