Osteogenesis Imperfecta: A Look into the Cerebellum of the Brtl Murine Model

Abstract

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare congenital connective tissue disorder linked to collagen I defects, commonly known for its skeletal implications. However, collagen fibers play several key roles also in the central nervous system (CNS) starting from CNS development, regulating axonal growth, synaptogenesis, and terminal differentiation of Schwann cells. Collagen I plays an active role in defining brain architecture and in the developing peripheral. Furthermore, collagen is associated with astrogliosis and scar formation, processes finely regulated by molecules that are also involved in the regulation of the oxidative stress pathway. The aim of this work was to evaluate possible alterations in the cerebellum of the Brtl mouse, a well characterized model of dominant OI, focusing on cerebellar morphology using hematoxylin-eosin and Picrosirius Red staining, both in bright-field and polarized light microscopy. Additionally, ultrastructural alterations in the different cerebellar neuronal populations were evaluated using transmission electron microscopy (TEM), along with the involvement of the oxidative stress pathway by analyzing the expression levels of specific REDOX markers, such as COX4, SOD2, GPX4, and NRF2. Our results clearly demonstrate morphological and ultrastructural changes in the cerebellum of OI mice, along with increased oxidative stress detected in different regions and cell populations of this CNS area, suggesting possible CNS damage driven by the mutated form of collagen I. This work represents the first report of strong morphological and ultrastructural alterations in several cerebellar areas of Brtl mice, as well as a direct impact on the oxidative stress pathway.

Keywords: Brtl mice; Cerebellum; Collagen; In vivo; Osteogenesis imperfecta; Oxidative stress.