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

Ilaria Zancan, Stefania Bellesso, Roberto Costa, Marika Salvalaio, Marina Stroppiano, Chrissy Hammond, Francesco Argenton, Mirella Filocamo, Enrico Moro

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1280-1294
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number5
DOIs
Publication statusPublished - Mar 1 2015

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Gaucher Disease
Catenins
Zebrafish
Osteogenesis
Oxidative Stress
Bone and Bones
Glucosylceramidase
Physiologic Calcification
Bone Resorption
Osteoblasts
Reactive Oxygen Species
Fibroblasts
Macrophages

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling. / Zancan, Ilaria; Bellesso, Stefania; Costa, Roberto; Salvalaio, Marika; Stroppiano, Marina; Hammond, Chrissy; Argenton, Francesco; Filocamo, Mirella; Moro, Enrico.

In: Human Molecular Genetics, Vol. 24, No. 5, 01.03.2015, p. 1280-1294.

Research output: Contribution to journalArticle

Zancan, Ilaria ; Bellesso, Stefania ; Costa, Roberto ; Salvalaio, Marika ; Stroppiano, Marina ; Hammond, Chrissy ; Argenton, Francesco ; Filocamo, Mirella ; Moro, Enrico. / Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 5. pp. 1280-1294.
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