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Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells

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 o...

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Autores principales: Kim, Dongkyu, Choi, Jieun, Han, Kyu-Min, Lee, Beom Hee, Choi, Jin-Ho, Yoo, Han-Wook, Han, Yong-Mahn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562349/
https://www.ncbi.nlm.nih.gov/pubmed/26347346
http://dx.doi.org/10.1186/s13287-015-0147-5
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author Kim, Dongkyu
Choi, Jieun
Han, Kyu-Min
Lee, Beom Hee
Choi, Jin-Ho
Yoo, Han-Wook
Han, Yong-Mahn
author_facet Kim, Dongkyu
Choi, Jieun
Han, Kyu-Min
Lee, Beom Hee
Choi, Jin-Ho
Yoo, Han-Wook
Han, Yong-Mahn
author_sort Kim, Dongkyu
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-015-0147-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-45623492015-09-09 Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells Kim, Dongkyu Choi, Jieun Han, Kyu-Min Lee, Beom Hee Choi, Jin-Ho Yoo, Han-Wook Han, Yong-Mahn Stem Cell Res Ther Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-015-0147-5) contains supplementary material, which is available to authorized users. BioMed Central 2015-09-07 /pmc/articles/PMC4562349/ /pubmed/26347346 http://dx.doi.org/10.1186/s13287-015-0147-5 Text en © Kim et al. 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Kim, Dongkyu
Choi, Jieun
Han, Kyu-Min
Lee, Beom Hee
Choi, Jin-Ho
Yoo, Han-Wook
Han, Yong-Mahn
Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title_full Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title_fullStr Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title_full_unstemmed Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title_short Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells
title_sort impaired osteogenesis in menkes disease-derived induced pluripotent stem cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562349/
https://www.ncbi.nlm.nih.gov/pubmed/26347346
http://dx.doi.org/10.1186/s13287-015-0147-5
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