期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 5, 页码 1280-1294出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu538
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资金
- Genzyme Generation Program
- Italian Ministry of Health (Ricerca Finalizzata) [GR-2008-1139743]
- Versus Arthritis [19476] Funding Source: researchfish
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 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.
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