Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling.

Abstract

Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD). Enhanced bone resorption by infiltrating macrophages has been proposed to lead to major bone defects. However, while more recent evidences support the hypothesis that osteoblastic bone formation is impaired, a clear pathogenetic mechanism has not been depicted yet. Here, by combining different molecular approaches, we show that Gba1 loss of function in zebrafish is associated with defective canonical Wnt signaling, impaired osteoblast differentiation and reduced bone mineralization. We also provide evidence that increased reactive oxygen species production precedes the Wnt signaling impairment, which can be reversed upon human GBA1 overexpression. Type 1 GD patient fibroblasts similarly exhibit reduced Wnt signaling activity, as a consequence of increased β-catenin degradation. Our results support a novel model in which a primary defect in canonical Wnt signaling antecedes bone defects in type 1 GD.

• Authors: Ilaria Zancan, Stefania Bellesso, Roberto Costa, Marika Salvalaio, Marina Stroppiano, Chrissy Hammond, Francesco Argenton, Mirella Filocamo, Enrico Moro
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 5 Pg. 1280-94 (Mar 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25326392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Biomarkers
• Reactive Oxygen Species
• beta Catenin
• Glucosylceramidase

Topics

• Animals
• Apoptosis
• Biomarkers (blood)
• Bone Resorption (genetics, metabolism)
• Bone and Bones (metabolism)
• Cell Differentiation
• Cell Proliferation
• Cloning, Molecular
• Disease Models, Animal
• Gaucher Disease (genetics, pathology)
• Gene Expression Profiling
• Gene Expression Regulation
• Genotyping Techniques
• Glucosylceramidase (genetics)
• Humans
• Osteoblasts (cytology, metabolism)
• Osteogenesis (genetics)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)
• Wnt Signaling Pathway
• Zebrafish (genetics, metabolism)
• beta Catenin (genetics, metabolism)