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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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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. |
format | Online Article Text |
id | pubmed-4562349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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