title: 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.affiliation: Department of Molecular Medicine.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zancan
authors.affiliation: Department Women's and Child's Health.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellesso
authors.affiliation: Department of Molecular Medicine.
authors.forename: Roberto
authors.initials: R
authors.lastname: Costa
authors.affiliation: Department Women's and Child's Health.
authors.forename: Marika
authors.initials: M
authors.lastname: Salvalaio
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche Istituto Giannina Gaslini, Genova 16147, Italy and.
authors.forename: Marina
authors.initials: M
authors.lastname: Stroppiano
authors.affiliation: Department of Biochemistry, Physiology & Pharmacology, University of Bristol, BS8 1TD Bristol, UK.
authors.forename: Chrissy
authors.initials: C
authors.lastname: Hammond
authors.affiliation: Department of Biology, University of Padova, I-35131 Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche Istituto Giannina Gaslini, Genova 16147, Italy and.
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.affiliation: Department of Molecular Medicine, moroe@bio.unipd.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D060005:Genotyping Techniques; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D051176:beta Catenin; D005962:Glucosylceramidase