TY - JOUR
T1 - Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling
AU - Zancan, Ilaria
AU - Bellesso, Stefania
AU - Costa, Roberto
AU - Salvalaio, Marika
AU - Stroppiano, Marina
AU - Hammond, Chrissy
AU - Argenton, Francesco
AU - Filocamo, Mirella
AU - Moro, Enrico
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84924502909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924502909&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu538
DO - 10.1093/hmg/ddu538
M3 - Article
C2 - 25326392
AN - SCOPUS:84924502909
VL - 24
SP - 1280
EP - 1294
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 5
ER -