Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells

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. We present in vitro modeling for impaired osteogenesis in MD using...

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Bibliographic Details
Published in:Stem cell research & therapy 2015-09, Vol.6 (1), p.160-160, Article 160
Main Authors: Kim, Dongkyu, Choi, Jieun, Han, Kyu-Min, Lee, Beom Hee, Choi, Jin-Ho, Yoo, Han-Wook, Han, Yong-Mahn
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Animals
Antigens, CD - genetics
Antigens, CD - metabolism
Bones
Cation Transport Proteins - genetics
Cells, Cultured
Comparative analysis
Copper-transporting ATPases
Density
Endoglin
Extracellular Matrix - metabolism
Genetic aspects
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - transplantation
Infant
Infant, Newborn
Menkes Kinky Hair Syndrome - genetics
Menkes Kinky Hair Syndrome - metabolism
Menkes Kinky Hair Syndrome - pathology
Mice
Mutation
Osteogenesis
Phosphatases
Physiological aspects
Protein-Lysine 6-Oxidase - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Stem cells
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Summary: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. 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. 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. Our findings indicate that ATP7A dysfunction contributes to retardation in MSC development and impairs osteogenesis in MD.
ISSN:1757-6512
1757-6512
DOI:10.1186/s13287-015-0147-5