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Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish
BACKGROUND: Mutations in the EXT genes disrupt polymerisation of heparan sulphates (HS) and lead to the development of osteochondroma, an isolated/sporadic- or a multifocal/hereditary cartilaginous bone tumour. Zebrafish (Danio rerio) is a very powerful animal model which has shown to present the sa...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004154/ https://www.ncbi.nlm.nih.gov/pubmed/24628984 http://dx.doi.org/10.1186/1750-1172-9-35 |
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author | Wiweger, Malgorzata I de Andrea, Carlos E Scheepstra, Karel W F Zhao, Zhe Hogendoorn, Pancras C W |
author_facet | Wiweger, Malgorzata I de Andrea, Carlos E Scheepstra, Karel W F Zhao, Zhe Hogendoorn, Pancras C W |
author_sort | Wiweger, Malgorzata I |
collection | PubMed |
description | BACKGROUND: Mutations in the EXT genes disrupt polymerisation of heparan sulphates (HS) and lead to the development of osteochondroma, an isolated/sporadic- or a multifocal/hereditary cartilaginous bone tumour. Zebrafish (Danio rerio) is a very powerful animal model which has shown to present the same cartilage phenotype that is commonly seen in mice model and patients with the rare hereditary syndrome, Multiple Osteochondroma (MO). METHODS: Zebrafish dackel (dak) mutant that carries a nonsense mutation in the ext2 gene was used in this study. A panel of molecular, morphological and biochemical analyses was used to assess at what step bone formation is affected and what mechanisms underlie changes in the bone formation in the ext2 mutant. RESULTS: During bone development in the ext2(-/-) zebrafish, chondrocytes fail to undergo terminal differentiation; and pre-osteoblasts do not differentiate toward osteoblasts. This inadequate osteogenesis coincides with increased deposition of lipids/fats along/in the vessels and premature adipocyte differentiation as shown by biochemical and molecular markers. Also, the ext2-null fish have a muscle phenotype, i.e. muscles are shorter and thicker. These changes coexist with misshapen bones. Normal expression of runx2 together with impaired expression of osterix and its master regulator - xbp1 suggest that unfolded protein responses might play a role in MO pathogenesis. CONCLUSIONS: Heparan sulphates are required for terminal differentiation of the cartilaginous template and consecutive formation of a scaffold that is needed for further bone development. HS are also needed for mesenchymal cell differentiation. At least one copy of ext2 is needed to maintain the balance between bone and fat lineages, but homozygous loss of the ext2 function leads to an imbalance between cartilage, bone and fat lineages. Normal expression of runx2 and impaired expression of osterix in the ext2(-/-) fish indicate that HS are required by osteoblast precursors for their further differentiation towards osteoblastic lineage. Lower expression of xbp1, a master regulator of osterix, suggests that HS affect the ‘unfolded protein response’, a pathway that is known to control bone formation and lipid metabolism. Our observations in the ext2-null fish might explain the musculoskeletal defects that are often observed in MO patients. |
format | Online Article Text |
id | pubmed-4004154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40041542014-04-30 Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish Wiweger, Malgorzata I de Andrea, Carlos E Scheepstra, Karel W F Zhao, Zhe Hogendoorn, Pancras C W Orphanet J Rare Dis Research BACKGROUND: Mutations in the EXT genes disrupt polymerisation of heparan sulphates (HS) and lead to the development of osteochondroma, an isolated/sporadic- or a multifocal/hereditary cartilaginous bone tumour. Zebrafish (Danio rerio) is a very powerful animal model which has shown to present the same cartilage phenotype that is commonly seen in mice model and patients with the rare hereditary syndrome, Multiple Osteochondroma (MO). METHODS: Zebrafish dackel (dak) mutant that carries a nonsense mutation in the ext2 gene was used in this study. A panel of molecular, morphological and biochemical analyses was used to assess at what step bone formation is affected and what mechanisms underlie changes in the bone formation in the ext2 mutant. RESULTS: During bone development in the ext2(-/-) zebrafish, chondrocytes fail to undergo terminal differentiation; and pre-osteoblasts do not differentiate toward osteoblasts. This inadequate osteogenesis coincides with increased deposition of lipids/fats along/in the vessels and premature adipocyte differentiation as shown by biochemical and molecular markers. Also, the ext2-null fish have a muscle phenotype, i.e. muscles are shorter and thicker. These changes coexist with misshapen bones. Normal expression of runx2 together with impaired expression of osterix and its master regulator - xbp1 suggest that unfolded protein responses might play a role in MO pathogenesis. CONCLUSIONS: Heparan sulphates are required for terminal differentiation of the cartilaginous template and consecutive formation of a scaffold that is needed for further bone development. HS are also needed for mesenchymal cell differentiation. At least one copy of ext2 is needed to maintain the balance between bone and fat lineages, but homozygous loss of the ext2 function leads to an imbalance between cartilage, bone and fat lineages. Normal expression of runx2 and impaired expression of osterix in the ext2(-/-) fish indicate that HS are required by osteoblast precursors for their further differentiation towards osteoblastic lineage. Lower expression of xbp1, a master regulator of osterix, suggests that HS affect the ‘unfolded protein response’, a pathway that is known to control bone formation and lipid metabolism. Our observations in the ext2-null fish might explain the musculoskeletal defects that are often observed in MO patients. BioMed Central 2014-03-14 /pmc/articles/PMC4004154/ /pubmed/24628984 http://dx.doi.org/10.1186/1750-1172-9-35 Text en Copyright © 2014 Wiweger et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 Wiweger, Malgorzata I de Andrea, Carlos E Scheepstra, Karel W F Zhao, Zhe Hogendoorn, Pancras C W Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title | Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title_full | Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title_fullStr | Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title_full_unstemmed | Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title_short | Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish |
title_sort | possible effects of ext2 on mesenchymal differentiation - lessons from the zebrafish |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004154/ https://www.ncbi.nlm.nih.gov/pubmed/24628984 http://dx.doi.org/10.1186/1750-1172-9-35 |
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