Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells

• Published in: Stem cell research & therapy Vol. 6; no. 1; p. 160
• Main Authors: Kim, Dongkyu, Choi, Jieun, Han, Kyu-Min, Lee, Beom Hee, Choi, Jin-Ho, Yoo, Han-Wook, Han, Yong-Mahn
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07-09-2015; BioMed Central
• 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; Japan
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-015-0147-5

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.