|ZFIN ID: ZDB-PUB-141019-3|
Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling
Zancan, I., Bellesso, S., Costa, R., Salvalaio, M., Stroppiano, M., Hammond, C., Argenton, F., Filocamo, M., Moro, E.
|Source:||Human molecular genetics 24(5): 1280-94 (Journal)|
|Registered Authors:||Argenton, Francesco, Bellesso, Stefania, Costa, Roberto, Hammond, Chrissy, Moro, Enrico, Salvalaio, Marika, Zancan, Ilaria|
|PubMed:||25326392 Full text @ Hum. Mol. Genet.|
Zancan, I., Bellesso, S., Costa, R., Salvalaio, M., Stroppiano, M., Hammond, C., Argenton, F., Filocamo, M., Moro, E. (2015) Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling. Human molecular genetics. 24(5):1280-94.
ABSTRACTLoss 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 (ROS) 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 beta catenin degradation. Our results support a novel model in which a primary defect in canonical Wnt signaling antecedes bone defects in type 1 GD.