Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells

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Introduction: Bone abnormalities, one of the primary manifestations of Menkes disease (MD), include a weakened bone matrix and low mineral density. However, the molecular and cellular mechanisms underlying these bone defects are poorly understood. Methods: We present in vitro modeling for impaired osteogenesis in MD using human induced pluripotent stem cells (iPSCs) with a mutated ATP7A gene. MD-iPSC lines were generated from two patients harboring different mutations. Results: The MD-iPSCs showed a remarkable retardation in CD105 expression with morphological anomalies during development to mesenchymal stem cells (MSCs) compared with wild-type (WT)-iPSCs. Interestingly, although prolonged culture enhanced CD105 expression, mature MD-MSCs presented with low alkaline phosphatase activity, reduced calcium deposition in the extracellular matrix, and downregulated osteoblast-specific genes during osteoblast differentiation in vitro. Knockdown of ATP7A also impaired osteogenesis in WT-MSCs. Lysyl oxidase activity was also decreased in MD-MSCs during osteoblast differentiation. Conclusions: Our findings indicate that ATP7A dysfunction contributes to retardation in MSC development and impairs osteogenesis in MD.
Publisher
BIOMED CENTRAL LTD
Issue Date
2015-09
Language
English
Article Type
Article
Keywords

LYSYL OXIDASE ACTIVITY; KINKY-HAIR SYNDROME; COPPER; DIFFERENTIATION; BONE; EXPRESSION; HYPOPHOSPHATASIA; MINERALIZATION; TRAFFICKING; OSTEOBLASTS

Citation

STEM CELL RESEARCH & THERAPY, v.6

ISSN
1757-6512
DOI
10.1186/s13287-015-0147-5
URI
http://hdl.handle.net/10203/203899
Appears in Collection
BS-Journal Papers(저널논문)
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